RELISTOR® (methylnaltrexone bromide)

Drug UPDATES: 
RELISTOR ® (methylnaltrexone bromide) tablets, for oral use
RELISTOR ® (methylnaltrexone bromide) injection, for subcutaneous use

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Initial U.S. Approval:  2008  [New tablet formulation - 7/2016]

Mechanism of Action:

INDICATIONS AND USAGE:
•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. ( 1.1)
•RELISTOR injection is 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. ( 1.2)

•Limitations of Use: Use beyond four months has not been studied in the advanced illness population.

DOSAGE AND ADMINISTRATION:
Administration Instructions (2.1)
•Be within close proximity to toilet facilities once administered.
•Discontinue if treatment with opioid pain medication is also discontinued.
•In adult patients with chronic non-cancer pain and OIC:

•RELISTOR has been shown to be efficacious in patients who have taken opioids for at least 4 weeks.
•Discontinue all maintenance laxative therapy before starting RELISTOR; may resume laxatives if there is a suboptimal response to RELISTOR after 3 days.
•Re-evaluate the continued need for RELISTOR when opioid regimen is changed to avoid adverse reactions.

•In patients with chronic non-cancer pain and OIC, take RELISTOR tablets with water on an empty stomach at least 30 minutes before the first meal of the day.

Dosing
For OIC in adult patients with chronic non-cancer pain ( 2.2):
•RELISTOR tablets: The recommended dosage is 450 mg once daily in the morning.
•RELISTOR injection: The recommended dosage is 12 mg subcutaneously once daily.

For OIC in adult patients with advanced illness ( 2.3):
•The pre-filled syringe is only for patients who require a RELISTOR injection dose of 8 mg or 12 mg. Use the vial for patients who require other doses of RELISTOR injection.
••RELISTOR injection: See Table 1 in the full prescribing information for the recommended dosage; administer one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

Dosage Adjustment
•See full prescribing information dosage adjustment in renal or hepatic impairment by indication. ( 2.4, 2.5)  PDF

Preparation and Administration of RELISTOR Injection (2.6)
•For subcutaneous use only.
•Inject in upper arm, abdomen or thigh. Rotate injection sites.

HOW SUPPLIED::
Tablets: 150 mg methylnaltrexone bromide.

Injection:
8 mg/0.4 mL methylnaltrexone bromide in single-dose pre-filled syringe.
12 mg/0.6 mL methylnaltrexone bromide in a single-dose pre-filled syringe, or single-dose vial.

RELISTOR (methylnaltrexone bromide) Subcutaneous Injection, a peripherally-acting mu-opioid receptor antagonist, is a sterile, clear and colorless to pale yellow aqueous solution. The chemical name for methylnaltrexone bromide is (R)-N-(cyclopropylmethyl) noroxymorphone methobromide. The molecular formula is C21H26NO4Br, and the molecular weight is 436.36.

Each 3 mL vial contains 12 mg of methylnaltrexone bromide in 0.6 mL of water. The excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride. During manufacture, the pH may have been adjusted with hydrochloric acid and/or sodium hydroxide.

Each 8 mg/0.4 mL pre-filled syringe (1 mL syringe) contains 8 mg of methylnaltrexone bromide in 0.4 mL of water. The excipients are 2.6 mg sodium chloride USP, 0.16 mg edetate calcium disodium USP, and 0.12 mg glycine hydrochloride.

Each 12 mg/0.6 mL pre-filled syringe (1 mL syringe) contains 12 mg of methylnaltrexone bromide in 0.6 mL of water. The excipients are 3.9 mg sodium chloride USP, 0.24 mg edetate calcium disodium USP, and 0.18 mg glycine hydrochloride.

Pharmacodynamics
Use of opioids induces slowing of gastrointestinal motility and transit. Antagonism of gastrointestinal mu-opioid receptors by methylnaltrexone bromide inhibits opioid-induced delay of gastrointestinal transit time in a dose-dependent manner in rats. The effects of methylnaltrexone bromide on central mu-opioid receptors were evaluated in a pharmacodynamic study in which subjects received a dose of remifentanil, sufficient to produce pupiliary constriction, followed by placebo, naloxone, or methylnaltrexone. Following remifentanil administration, the methylnaltrexone and placebo groups showed no change in pupiliary constriction while the naloxone group showed a marked change over the time interval tested.

• If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician.
• Rare cases of gastrointestinal (GI) perforation have been reported in advanced illness patients. Use RELISTOR with caution in patients with known or suspected lesions of the GI tract.

The most common (> 5%) adverse reactions reported with RELISTOR are abdominal pain, flatulence, nausea, dizziness, diarrhea and hyperhidrosis.

RELISTOR should be injected in the upper arm, abdomen or thigh.

Dosing
RELISTOR is administered as a subcutaneous injection. The usual schedule is one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

The recommended dose of RELISTOR is 8 mg for patients weighing 38 to less than 62 kg (84 to less than 136 lb) or 12 mg for patients weighing 62 to 114 kg (136 to 251 lb). Patients whose weight falls outside of these ranges should be dosed at 0.15 mg/kg. See the table below to determine the correct injection volume. The pre-filled syringe is designed to deliver a fixed dose; therefore, patients requiring dosing calculated on a mg/kg basis should not be prescribed pre-filled syringes.

Use in Patients with Severe Renal Impairment
In patients with severe renal impairment (creatinine clearance less than 30 mL/min), dose reduction of RELISTOR by one-half is recommended.

The pre-filled syringe is designed to deliver a fixed dose; therefore, patients with severe renal impairment should not be prescribed pre-filled syringes unless their body weight calculated dose is 8 mg or 12 mg.

Preparation for Injection
RELISTOR is a sterile, clear, and colorless to pale yellow aqueous solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If any of these are present, the vial should not be used.

Preparation of RELISTOR Using the Single-use Vial
Once drawn into the syringe, if immediate administration is not possible, store at ambient room temperature and administer within 24 hours.

Preparation of RELISTOR Using the Single-use Pre-filled Syringe
Do not remove the pre-filled syringe from the tray until ready to administer.

RELISTOR is available in the following dosage forms and strengths. Only patients requiring an 8 mg or 12 mg dose should be prescribed pre-filled syringes.

Single-use vial containing 12 mg/0.6 mL solution for subcutaneous injection.

Single-use pre-filled syringe containing 8 mg/0.4 mL solution for subcutaneous injection, with a 29-gauge x half-inch fixed needle and a needle guard.

Single-use pre-filled syringe containing 12 mg/0.6 mL solution for subcutaneous injection, with a 29-gauge x half-inch fixed needle and a needle guard.

Storage
RELISTOR® should be stored at 20-25ºC (68-77ºF); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light.

Under license from:
Progenics Pharmaceuticals, Inc.
Tarrytown, NY 10591

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 12 mg/0.6 mL - VIAL
RELISTOR®
(methylnaltrexone bromide)
Subcutaneous Injection
12 mg/0.6 mL per vial
For Subcutaneous Injection Only

Sterile Single Use Vial
Discard After Use
Rx only
Manufactured for Salix Pharmaceuticals, Inc.
Under license from Progenics Pharmaceuticals