Alvimopan: Package Insert and Label Information

ALVIMOPAN- alvimopan capsule
Actavis Pharma, Inc.

WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY

There was a greater incidence of myocardial infarction in alvimopan-treated patients compared to placebo-treated patients in a 12-month clinical trial, although a causal relationship has not been established. In short-term trials with alvimopan, no increased risk of myocardial infarction was observed [see Warnings and Precautions (5.1)].

Because of the potential risk of myocardial infarction with long-term use, alvimopan is available only through a restricted program for short-term use (15 doses) under a Risk Evaluation and Mitigation Strategy (REMS) called the Alvimopan REMS Program [see Warnings and Precautions (5.1, 5.2)].

1 INDICATIONS AND USAGE

Alvimopan capsules are indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis.

2 DOSAGE AND ADMINISTRATION

For hospital use only. The recommended adult dosage of alvimopan capsules is 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery until discharge for a maximum of 7 days. Patients should not receive more than 15 doses of alvimopan capsules.

Alvimopan capsules can be taken with or without food [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Capsules: 12 mg white to off-white, hard gelatin capsules printed with “2312 ” on body of the capsule.

4 CONTRAINDICATIONS

Alvimopan capsules are contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking alvimopan capsules [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Potential Risk of Myocardial Infarction with Long-Term Use

There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic non-cancer pain (alvimopan 0.5 mg, n=538; placebo, n=267).

In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan in patients treated with opioids for chronic pain, nor in patients treated within the surgical setting, including patients undergoing surgeries that included bowel resection who received alvimopan 12 mg twice daily for up to 7 days (the indicated dose and patient population; alvimopan 12 mg, n=1,142; placebo, n=1,120). A causal relationship with alvimopan with long-term use has not been established.

Alvimopan capsules are available only through a program under a REMS that restricts use to enrolled hospitals [see Warnings and Precautions (5.2)].

5.2 Alvimopan REMS Program

Alvimopan capsules are available only through a program called the Alvimopan REMS Program that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of alvimopan capsules [see Warnings and Precautions (5.1)].

Notable requirements of the Alvimopan REMS Program include the following:

Alvimopan capsules are available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the Alvimopan REMS Program may use alvimopan capsules.

To enroll in the Alvimopan REMS Program, an authorized hospital representative must acknowledge that:

  • hospital staff who prescribe, dispense, or administer alvimopan capsules have been provided the educational materials on the need to limit use of alvimopan capsules to short-term, inpatient use;

  • patients will not receive more than 15 doses of alvimopan capsules; and

  • alvimopan capsules will not be dispensed to patients after they have been discharged from the hospital.

Further information is available at www.alvimopanREMS.com or 1-800-278-0340.

5.3 Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients

Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists, such as alvimopan. Since alvimopan acts peripherally, clinical signs and symptoms of increased sensitivity would be related to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Patients receiving more than 3 doses of an opioid within the week prior to surgery were not studied in the postoperative ileus clinical trials. Therefore, if alvimopan is administered to these patients, they should be monitored for gastrointestinal adverse reactions. Alvimopan is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking alvimopan [see Contraindications (4)].

5.4 Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment

Patients with severe hepatic impairment may be at higher risk of serious adverse reactions (including dose-related serious adverse reactions) because up to 10-fold higher plasma concentrations of alvimopan have been observed in such patients compared with patients with normal hepatic function. Therefore, the use of alvimopan is not recommended in this population [see Use in Specific Populations (8.6)].

5.5 End-Stage Renal Disease

No studies have been conducted in patients with end-stage renal disease. Alvimopan is not recommended for use in these patients [see Use in Specific Populations (8.7)].

5.6 Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction

No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. Alvimopan is not recommended for use in these patients.

5.7 Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses

Alvimopan has not been studied in patients having pancreatic or gastric anastomosis. Therefore, alvimopan is not recommended for use in these patients.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Potential Risk of Myocardial Infarction with Long-Term Use [see Warnings and Precautions (5.1)]
  • Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients [see Warnings and Precautions (5.3)]
  • Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment [see Warnings and Precautions (5.4)]
  • Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction [see Warnings and Precautions (5.6)]
  • Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses [see Warnings and Precautions (5.7)]

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 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 alvimopan 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 alvimopan 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 alvimopan-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 (alvimopan, 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.

7 DRUG INTERACTIONS

7.1 Effects of Alvimopan on Intravenous Morphine

Coadministration of alvimopan does not appear to alter the pharmacokinetics of morphine and its metabolite, morphine-6-glucuronide, to a clinically significant degree when morphine is administered intravenously. Dosage adjustment for intravenously administered morphine is not necessary when it is coadministered with alvimopan.

7.2 Effects of Concomitant Acid Blockers or Antibiotics

A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers (proton pump inhibitors (PPIs), histamine-2 (H2 ) receptor antagonists) or antibiotics. No dosage adjustments are necessary in patients taking acid blockers or antibiotics with alvimopan.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data regarding use of alvimopan in pregnant women are limited, and are insufficient to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

No fetal harm was observed in animal reproduction studies with oral administration of alvimopan during organogenesis to pregnant rats at doses 68 to 136 times the recommended human oral dose, or with intravenous administration during organogenesis to pregnant rats and pregnant rabbits at doses 3.4 to 6.8 times, and 5 to 10 times, respectively, the recommended human oral dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Embryo-fetal studies were performed in pregnant rats during organogenesis (gestation days 7 through 19, or 20) at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on body surface area) and 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). A study in pregnant rabbits during organogenesis (gestation days 6 through 18) at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on body surface area) revealed no evidence of harm to the fetus due to alvimopan.

In an intravenous pre- and postnatal development study (gestation day 7 through lactation day 20) in rats, alvimopan did not cause any adverse effect on pre- and postnatal development at doses up to 10 mg/kg/day (about 6.8 times the recommended human oral dose based on body surface area).

8.2 Lactation

Risk Summary

There are no data on the presence of alvimopan in human milk, the effects on the breastfed infant, or the effects on milk production. Alvimopan and its ‘metabolite’ are detected in the milk of lactating rats following intravenous administration (see Data). It is unknown if alvimopan is present in rat milk following oral administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for alvimopan and any potential adverse effects on the breastfed child from alvimopan or from the underlying maternal condition.

Data

Following intravenous administration of alvimopan to lactating rats at 10 mg/kg/day, concentrations of alvimopan and its ‘metabolite’ in the milk were approximately 15- and 0.11-fold, respectively, the concentration of alvimopan in maternal plasma at 1-hour post-dose.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in 6 clinical efficacy studies treated with alvimopan 12 mg or placebo, 46% were 65 years of age and over, while 18% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment based on increased age is required [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Alvimopan is not recommended for use in patients with severe hepatic impairment.

Dosage adjustment is not required for patients with mild-to-moderate hepatic impairment. Patients with mild-to-moderate hepatic impairment should be closely monitored for possible adverse reactions (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high alvimopan or ‘metabolite’ concentrations, and alvimopan should be discontinued if adverse reactions occur [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Alvimopan is not recommended for use in patients with end-stage renal disease. Dosage adjustment is not required for patients with mild-to-severe renal impairment, but they should be monitored for adverse reactions. Patients with severe renal impairment should be closely monitored for possible adverse reactions (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high alvimopan or ‘metabolite’ concentrations, and alvimopan should be discontinued if adverse reactions occur [see Clinical Pharmacology (12.3)].

8.8 Race/Ethnicity

No dosage adjustment is necessary in Black, Hispanic, and Japanese patients. However, the exposure to alvimopan in Japanese healthy male subjects was approximately 2-fold greater than in Caucasian subjects. Japanese patients should be closely monitored for possible adverse reactions (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high alvimopan or ‘metabolite’ concentrations, and alvimopan should be discontinued if adverse reactions occur [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

Alvimopan capsules contain alvimopan, an opioid antagonist. Chemically, alvimopan is the single stereoisomer [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate. It has the following structural formula:

1
(click image for full-size original)

Alvimopan is a white to light beige powder with a molecular weight of 460.54, and the empirical formula is C25 H32 N2 O4 •2H2 O. It has a solubility of <0.1 mg/mL in water or buffered solutions between pH 3.0 and 9.0, 1 to 5 mg/mL in buffered solutions at pH 1.2, and 10 to 25 mg/mL in aqueous 0.1 N sodium hydroxide. At physiological pH, alvimopan is zwitterionic, a property that contributes to its low solubility.

Alvimopan capsules for oral administration contain 12 mg of alvimopan on an anhydrous basis suspended in the inactive ingredient polyethylene glycol 3350. The capsule shell contains gelatin, sodium lauryl sulfate, and titanium dioxide. The imprinting ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution.

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