Entereg

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

Some people had heart attacks while taking alvimopan long-term during clinical studies. It is not clear whether alvimopan is the actual cause of heart attack. Call your doctor at once if you have heart attack symptoms, such as:

• chest pain or pressure;
• pain spreading to your jaw or shoulder;
• anxiety, nausea, sweating.

Common side effects may include:

• indigestion, stomach pain;
• nausea, vomiting; or
• diarrhea.

You may be more likely to have unpleasant effects on your stomach if you have recently used any type of narcotic (opioid) medicine.

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.

Alvimopan is given only in a hospital for a short period of time.

You will receive your first dose of alvimopan up to 5 hours before your surgery. You will then be given additional doses 2 times per day for up to 7 days.

This medicine should not be used for longer than 7 days after your surgery.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Because you will receive alvimopan in a clinical setting, you are not likely to miss a dose.

Pregnancy Category: B

Lactation: excretion in milk unknown; use with caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Postoperative Ileus

Acceleration of upper and lower GI recovery following partial large or small bowel resection with primary anastomosis.1 2 3 9 10 11 12 19

Efficacy for management of postoperative ileus in women undergoing total abdominal hysterectomy† under general anesthesia not established to date.1 8

Contraindications

• Therapeutic doses of opiates for >7 consecutive days immediately prior to alvimopan administration.1 2

Warnings/Precautions

Restricted Distribution Program

Only for short-term (15 doses) use in hospitalized patients.1 2 For use only by hospitals enrolled in the EASE program.1 2 (See Restricted Distribution Program under Dosage and Administration.)

MI

May be associated with increased incidence of MI when used long term;1 2 3 4 7 not found with short-term (i.e., ≤7 days) use following bowel resection.1 3 4 Causal relationship not established.1 (See Boxed Warning and see Restricted Distribution Program under Dosage and Administration.)

Recent Opiate Use

Increased sensitivity to alvimopan possible with recent exposure to opiates; manifests principally as GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea).1 Use caution in patients who have received >3 doses of an opiate within 1 week prior to surgery.1 (See Contraindications under Cautions.)

Bowel Obstruction

Not recommended for use in patients undergoing surgical correction of complete bowel obstruction.1

Specific Populations

Category B.1

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Safety and efficacy not established in children <18 years of age.1

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 15

Slight increase in plasma alvimopan concentrations possible in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 Monitor for adverse effects (e.g., diarrhea, abdominal pain or cramping) that may indicate alvimopan or metabolite accumulation; discontinue if such effects occur.1 15 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 8 15 Substantially increased plasma concentrations possible.1

Monitor for possible adverse effects in patients with renal impairment.1 15 Closely monitor those with severe renal impairment for adverse effects (e.g., diarrhea, abdominal pain or cramping) that may indicate elevated alvimopan or metabolite concentrations; discontinue if such effects occur.1 15 (See Renal Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Not studied in patients with end-stage renal disease.1 Use not recommended.1

Common Adverse Effects

Constipation,1 hypokalemia,1 11 flatulence,1 dyspepsia,1 anemia,1 back pain,1 urinary retention.1

Absorption

Bioavailability

Absolute bioavailability averages 6% (range 1–19%).1 7 11

Food

High-fat meal decreases rate and extent of absorption.1

Distribution

Extent

Does not readily cross blood-brain barrier.1 6 7 14 15 16

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Alvimopan: 80%.1 Metabolite: 94%.1 Bound to albumin.1

Elimination

Metabolism

Metabolized by intestinal flora to active metabolite;1 metabolite not required for pharmacologic activity.8 16

No substantial hepatic metabolism.1

Elimination Route

Excreted principally via biliary secretion (65%) and in the urine (35%).1 16

Half-life

10–17 hours.1

Special Populations

Exposure to alvimopan is 1.5-fold to twofold higher in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); accumulation possible after multiple doses.1 Exposure may be increased approximately tenfold in patients with severe hepatic impairment (Child-Pugh class C).1

Exposure to metabolite is twofold to fivefold higher in patients with moderate or severe renal impairment.1 Alvimopan half-life is prolonged in patients with severe renal impairment.1 Accumulation of alvimopan and metabolite is possible after multiple doses in patients with severe renal impairment.1 Not studied in patients with end-stage renal disease.1

Exposure to alvimopan is twofold higher in patients with quiescent Crohn’s disease relative to healthy individuals or those with active Crohn’s disease; metabolite concentrations are lower in patients with Crohn’s disease.1

Storage

Oral

25°C (may be exposed to 15–30°C).1

• Importance of informing clinicians of long-term or intermittent opiate therapy, including any use of opiates in the week prior to receiving alvimopan.1 Potential for alvimopan to precipitate GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea) in patients who have recently received opiate therapy; importance of informing clinician if such adverse events occur.1

• Importance of informing patients that alvimopan is indicated for hospital use only and for no more than 7 days following bowel resection.1

• Advise patients that the most common adverse effects of alvimopan are constipation, dyspepsia, and flatulence.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

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 compared directly with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described below reflect exposure to Entereg 12 mg in 1,793 patients in 10 placebo-controlled studies. The population was 19 to 97 years old, 64% were female, and 84% were Caucasian; 64% were undergoing a surgery that included bowel resection. The first dose of Entereg was administered 30 minutes to 5 hours before the scheduled start of surgery and then twice daily until hospital discharge (or for a maximum of 7 days of postoperative treatment).

Among Entereg-treated patients undergoing surgeries that included a bowel resection, the most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo was dyspepsia (Entereg, 1.5%; placebo, 0.8%). Adverse reactions are events that occurred after the first dose of study medication treatment and within 7 days of the last dose of study medication or events present at baseline that increased in severity after the start of study medication treatment.

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

NDC 67919-020-10

Entereg®
(alvimopan) capsules

12 mg

Rx only

HOSPITAL USE ONLY

30 capsules
12 mg unit dose pack

CUBIST

Entereg (alvimopan) reduces certain side effects of narcotic medicines that are often used to prevent pain caused by surgery. Narcotic medicine can cause stomach pain, bloating, nausea, vomiting, and constipation. These side effects can delay recovery in patients undergoing gastrointestinal surgery.

Entereg helps prevent these side effects without reducing the pain-relieving effects of the narcotic.

Entereg is used to help restore normal digestive functioning after surgery to remove a portion of your intestine. This medicine is available only under a special program for short-term use (no more than 15 doses). You must be registered in the program and understand the risks and benefits of taking this medicine.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.