RELISTOR: Demonstrated Safety Profile Without Significant Pharmacokinetic Drug-to-Drug Interactions1

RELISTOR has not been shown to significantly inhibit or induce the activity of the CYP3A4 pathway.1*

*The clinical significance of these in vitro data is unknown.

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.

 

Safety was evaluated in 4 double-blind, placebo-controlled trials as well as open-label studies, including:

  • Adult patients with chronic non-cancer pain (CNCP)1
    • 4-week double-blind, placebo-controlled trial (401 patients): RELISTOR tablets
    • 4-week double-blind, placebo-controlled period (312 patients): RELISTOR injection
    • 48-week open-label study (1034 patients): RELISTOR injection
  • Adult patients with advanced illness receiving palliative care1
    • Two double-blind, placebo-controlled trials (287 patients): RELISTOR injection
    • Two open-label extension studies of up to 4 months (103 patients): RELISTOR injection

RELISTOR had no significant effect on key safety considerations1

Consideration Effect No Effect
Key CYP450 isozyme activity, including the CYP3A4 pathway
Daily opioid dose from baseline†‡
Pain scores from baseline†§

In advanced illness trials.

Daily opioid use did not vary in RELISTOR-treated patients.

§In RELISTOR-treated patients, there were no clinically relevant differences in pain scores.

Most common adverse reactions in adult patients with opioid-induced constipation (OIC) and CNCP: RELISTOR tablets1

Adverse reactionsll in 4-week double-blind, placebo-controlled period of clinical study of RELISTOR tablets in adult patients with OIC and CNCP1

Adverse Reaction RELISTOR Tablets (n=200) Placebo (n=201)
Abdominal pain 14% 10%
Diarrhea 5% 2%
Headache 4% 3%
Abdominal distention 4% 2%
Vomiting 3% 2%
Hyperhidrosis 3% 1%
Anxiety 2% 1%
Muscle spasms 2% 1%
Rhinorrhea 2% 1%
Chills 2% 0%

llAdverse reactions occurring in ≥2% of patients receiving RELISTOR tablets 450 mg once daily and at an incidence greater than placebo.

Most common adverse reactions in adult patients with OIC and CNCP: RELISTOR injection1

Adverse reactions in a 4-week double-blind, placebo-controlled period of clinical study of RELISTOR injection in adult patients with OIC and CNCP1

Adverse Reaction RELISTOR Injection
12 mg once daily (n=150)
Placebo (n=162)
Abdominal pain 21% 7%
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 SC once daily and at an incidence greater than placebo.

Most common adverse reactions in adult patients with OIC and advanced illness1

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

Adverse Reaction RELISTOR Injection (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 injection (0.075, 0.15, and 0.3 mg/kg) and at an incidence greater than placebo.

Indications

  • RELISTOR is an opioid antagonist. RELISTOR tablets and RELISTOR injection are indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain.
  • RELISTOR injection is also indicated for the treatment of OIC in adults with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Limitations of Use: Use beyond four months has not been studied in the advanced illness population.

IMPORTANT SAFETY INFORMATION - RELISTOR tablets and RELISTOR injection

  • RELISTOR tablets and injection are contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.
  • 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.
  • If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider.
  • 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.
  • 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.
  • The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the potential for serious adverse reactions, including opioid withdrawal, in breastfed infants, advise women that breastfeeding is not recommended during treatment with RELISTOR. 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.
  • A dosage reduction of RELISTOR tablets and RELISTOR injection is recommended in patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute as estimated by Cockcroft-Gault). No dosage adjustment of RELISTOR tablets or RELISTOR injection is needed in patients with mild renal impairment.
  • A dosage reduction of RELISTOR tablets is recommended in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. No dosage adjustment of RELISTOR tablets is needed in patients with mild hepatic impairment (Child-Pugh Class A). No dosage adjustment of RELISTOR injection is needed for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, monitor for methylnaltrexone-related adverse reactions.
  • In the clinical studies, the most common adverse reactions were:
    • OIC in adult patients with chronic non-cancer pain
      • RELISTOR tablets (≥2% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (14%), diarrhea (5%), headache (4%), abdominal distention (4%), vomiting (3%), hyperhidrosis (3%), anxiety (2%), muscle spasms (2%), rhinorrhea (2%), and chills (2%).
      • RELISTOR injection (≥1% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (21%), nausea (9%), diarrhea (6%), hyperhidrosis (6%), hot flush (3%), tremor (1%), and chills (1%).
    • OIC in adult patients with advanced illness
      • RELISTOR injection (≥5% of RELISTOR patients and at a greater incidence than placebo): abdominal pain (29%), flatulence (13%), nausea (12%), dizziness (7%), and diarrhea (6%).

To report SUSPECTED ADVERSE REACTIONS, contact Salix at 1-800-508-0024 or FDA at 1-800-FDA-1088 or www.fda.gov/Safety/MedWatch/

Please click here for full Prescribing Information for RELISTOR tablets and RELISTOR injection.

REFERENCE:

  1. RELISTOR (methylnaltrexone bromide) Prescribing Information. Bridgewater, NJ: Salix Pharmaceuticals.