RELISTOR helps provide reliable and rapid
relief from opioid-induced constipation (OIC)1

In a clinical study of RELISTOR (N=150) for the treatment of OIC in adult patients with chronic non-cancer pain:

  • 6 out of 10 RELISTOR patients (n=88) had at least 3 Spontaneous Bowel Movements (SBMs) per week
  • One-third of RELISTOR patients experienced an SBM within 4 hours of their
    first dose

IMPORTANT SAFETY INFORMATION

RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

OPIOID-INDUCED CONSTIPATION
MAY HAVE A BIGGER IMPACT THAN
YOU MIGHT REALIZE
  • Opioids used to manage chronic non-cancer pain can cause constipation and discomfort in the gastrointestinal (GI) tract, known as OIC2,3
  • When traditional therapies and lifestyle changes provide limited relief, your patients may be experiencing OIC3

OIC is Common and Persistent2

41% of patients taking opioids for chronic non-cancer pain reported being constipated*

%
Results based on a systematic review including 673 surveyed patients from 8 trials designed to assess the safety and efficacy of opioid therapy for chronic pain.

Pain Management May be Compromised by OIC3

Effect on pain management

  • Approximately one-third of patients on daily opioids reported altering their opioid dose to ease a bowel movement (BM)†
  • 92% of these patients reported increased pain after doing so
Report is based on a survey of 322 chronic pain patients. Participants altered their oral opioid treatment by skipping a dose, decreasing the dose, or stopping opioid treatment to ease a BM.

Opioid-dose
alteration

No reported
opioid-dose alteration

IMPORTANT SAFETY INFORMATION

Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie's syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn's disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.

RELISTOR® (methylnaltrexone bromide) SUBCUTANEOUS INJECTION HELPS PROVIDE RELIABLE AND RAPID RELIEF
FROM OPIOID-INDUCED CONSTIPATION

IN ADULT PATIENTS WITH OIC ON OPIOIDS FOR CHRONIC
NON-CANCER PAIN

IN A CLINICAL STUDY

  • RELISTOR increased the number of weekly SBMs1,‡
SBM occurring without the use of rescue laxatives.

Percentage of patients with at least
3 SBMs per week1

PERCENTAGE OF PATIENTS
WITH BASELINE IMPROVEMENT

      70
      65
      60
      55
      50
      45
      40
      35
      30
      25
      20
      15
      10
      5
      0

59%

38%

P<0.001

SBM = spontaneous bowel movement.

RELISTOR 12 mg once daily (n=150)

Placebo (n=162)

One-Third of Adult Patients With OIC on Opioids for Chronic
Non-Cancer Pain Taking RELISTOR Experienced an SBM§ Within 4 Hours of Their First Dose1


SBM occurring without the use of rescue laxatives.

Percentage of patients experiencing
an SBM within 4 hours1


PERCENTAGE OF PATIENTS

      35
      30
      25
      20
      15
      10
      5
      0

33%

10%

P<0.001

SBM = spontaneous bowel movement.

RELISTOR 12 mg once daily (n=150)

Placebo (n=162)

Study Design

  • Patients with chronic non-cancer pain
  • In a 4-week, double-blind, randomized, placebo-controlled phase 3 study, the efficacy of RELISTOR was evaluated in 312 patients (150 RELISTOR 12 mg once daily, 162 placebo) with chronic non-cancer pain for which they were taking opiates. All patients had OIC, defined as <3 SBMs per week and ≥1 additional symptom of constipation1

IN ADULT PATIENTS WITH ADVANCED ILLNESS ON PALLIATIVE CARE WITH OIC

IN CLINICAL STUDIES

  • 62% and 48% of patients treated with RELISTOR had a BM within 4 hours of the first injection in 2 studies1,4
  • In both studies, approximately 30% of patients reported laxation within
    30 minutes of a dose of RELISTOR1,||
Defined as rescue-free BM.

Study Designs

  • Patients with advanced illness
  • One study was a multicenter, double-blind, randomized, placebo-controlled study, in which the efficacy of RELISTOR was evaluated in 154 patients
    (102 RELISTOR, 52 placebo) with advanced illness on palliative care with OIC1
  • Another study was a 2-week, double-blind, randomized, placebo-controlled trial followed by a subsequent 3-month, open-label extension study. The efficacy and safety of RELISTOR was evaluated in 133 patients (62 RELISTOR,
    71 placebo) with terminal disease1

IMPORTANT SAFETY INFORMATION

If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician.

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal.

RELISTOR® (methylnaltrexone bromide) SUBCUTANEOUS INJECTION HAS A
WELL-ESTABLISHED SAFETY PROFILE

SAFETY PROFILE OF RELISTOR IN ADULT PATIENTS WITH OIC
AND CHRONIC NON-CANCER PAIN

Adverse reactions in a 4-week, double-blind, placebo-controlled period of clinical study of RELISTOR in adult patients with OIC and chronic non-cancer pain1

ADVERSE REACTION RELISTOR 12 mg ONCE DAILY (n=150) PLACEBO (n=162)
Abdominal Pain 21% 6%
Nausea 9% 6%
Diarrhea 6% 4%
Hyperhidrosis 6% 1%
Hot Flush 3% 2%
Tremor 1% <1%
Chills 1% 0%
Adverse reactions occurring in ≥1% of patients receiving RELISTOR 12 mg once daily at an incidence greater than placebo.


  • The safety of RELISTOR was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with OIC and chronic non-cancer pain1
  • The adverse reactions seen in this study were similar to those observed during the 4-week, double-blind period of the first study

SAFETY PROFILE OF RELISTOR IN ADULT PATIENTS WITH OIC
AND ADVANCED ILLNESS

Adverse reactions# from all doses in double-blind, placebo-controlled, clinical studies of RELISTOR in adult patients with OIC and advanced illness1

ADVERSE REACTION RELISTOR (n=165) PLACEBO (n=123)
Abdominal Pain 29% 10%
Flatulence 13% 6%
Nausea 12% 5%
Dizziness 7% 2%
Diarrhea 6% 2%
Adverse reactions occurring in ≥5% of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo.

IMPORTANT SAFETY INFORMATION

Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

RELISTOR may precipitate opioid withdrawal in a fetus and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In nursing mothers, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

RELISTOR® (methylnaltrexone bromide) SUBCUTANEOUS INJECTION IS AVAILABLE IN
A PREFILLED SYRINGE

Only adult patients requiring an 8-mg or 12-mg dose should be prescribed prefilled syringes.

SUBCUTANEOUS INJECTION
29

– gauge needle

SEVERE RENAL IMPAIRMENT

Adult patients with severe renal impairment (creatinine clearance of <30 mL/min) should not use a prefilled syringe. Reduce the dose by one-half and use vial and syringe.

Recommended Dosing for OIC in Adult Patients With Chronic Non-Cancer Pain

12mg

Subcutaneously, once daily

Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk for opioid withdrawal.

Weight-Based Dosing for OIC in Adult Patients with Advanced Illness1

In adult patients with severe renal impairment (creatinine clearance <30 mL/min as estimated by Cockcroft-Gault), dose reduction of RELISTOR by one-half is recommended using vial and syringe only. No dosage adjustment is recommended for adult patients with mild to moderate renal impairment.

38kg

62kg

114kg

Weight of adult patient

 <38 kg 38 kg to <62 kg 62 kg to 114 kg >114kg

Subcutaneous dose

 0.15 mg/kg 8 mg 12 mg 0.15 mg/kg

Injection volume

 See below** 0.4 mL 0.6 mL See below**
The injection volume for these patients should be calculated using the following method: Multiply the patient weight in kilograms by 0.0075 and round up the volume to the nearest 0.1 mL.

IMPORTANT SAFETY INFORMATION

In clinical studies, serious and important adverse reactions were:
  • Gastrointestinal perforation
  • Severe or persistent diarrhea
  • Opioid withdrawal

In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.

In clinical studies in adult patients with opioid-induced constipation and advanced illness, the most common adverse reactions (≥ 5%) were abdominal pain, flatulence, nausea, dizziness, and diarrhea.

Company:
 Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC.
Pharmacologic
class:
 Opioid antagonist (peripheral).
Active
IngRedient:
 Methylnaltrexone bromide 8 mg/0.4 mL, 12 mg/0.6 mL; solution for subcutaneous (SC) injection.
Indications:

The treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

The treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.
ADULTS:
 Chronic non-cancer pain: Discontinue all maintenance laxatives prior to initiation; may be used if suboptimal methylnaltrexone response after 3 days. Reevaluate if opioid regimen is changed. Give 12 mg once daily.
Advanced illness: Give once every other day as needed (max 1 dose/24 hours). <38 kg or >114 kg: 0.15 mg/kg. 38 kg–<62 kg: 8 mg. 62 kg–114 kg: 12 mg. Severe renal impairment (CrCl<30 mL/min): reduce dose by ½. Prefilled syringes: use only for 8 mg or 12 mg fixed doses.

Give by SC injection in upper arm, abdomen, or thigh; rotate injection sites.
CHILDREN:
 Safety and effectiveness have not been established in pediatric patients <18 years.
Contraindications:
 Known or suspected GI obstruction and at increased risk of recurrent obstruction.
Safety
Considerations:
 Discontinue if concurrent opioid pain medication is also discontinued. GI perforation; monitor for severe, persistent, or worsening abdominal pain; discontinue if occurs. Discontinue if severe or persistent diarrhea occurs. Increased risk of opioid withdrawal and/or reduced analgesia in those with blood-brain barrier disruptions; monitor for symptoms. Bowel movement may occur within 30 minutes of dosing. Pregnancy (Cat. C). Nursing mothers: not recommended.
Interactions:
 Potential additive effects and increased risk of opioid withdrawal with concomitant use of other opioid antagonists; avoid. In vitro, did not significantly inhibit or induce the activity of cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. In vitro, did not induce the enzymatic activity of CYP2E1.
Adverse
reactions:
 Serious and important adverse reactions include:
Gastrointestinal perforation, severe or persistent diarrhea, opioid withdrawal.

Most common adverse events include:
Chronic non-cancer pain: Abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, chills.
Advanced illness: Abdominal pain, flatulence, nausea, dizziness, diarrhea.
How
Supplied:
 Single-use vial (12 mg/0.6 mL)—1 per carton; Prefilled syringes (8 mg/0.4 mL)—7 per carton; Prefilled syringes (12 mg/0.6 mL)—1 per carton; Prefilled syringes (12 mg/0.6 mL)—7 per carton.
MPR Monograph © 2016 Haymarket Media, Inc. All rights reserved.
REFERENCES
  1. RELISTOR [prescribing information]. Raleigh, NC: Salix Pharmaceuticals; 2014.
  2. Kalso E, Edwards JE, Moore RA, et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112(3):372-380.
  3. Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med. 2009;10(1):35-42.
  4. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol. 2009;7(1):39-46.

RELISTOR is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.
All other product/brand names are trademarks of their respective owners.

REL.0181.USA.15

This MPR Prescribing Alert® is produced as a basic reminder of important information for healthcare professionals. Readers are advised to consult manufacturers and specialists if questions arise about specific products, treatments, or diseases. The publisher and editors do not assume liability for any errors or omissions. MPR and MPR Prescribing Alert® are registered trademarks of Haymarket Media, Inc.

© 2016 Haymarket Media, Inc.

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