Methylnaltrexone Bromide

FDA Drug Information • Also known as: Relistor

Brand Names: Relistor
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION RELISTOR ® (methylnaltrexone bromide) is a mu-opioid receptor antagonist. The chemical name for methylnaltrexone bromide is ( R )- N -(cyclopropylmethyl) noroxymorphone methobromide. The molecular formula is C 21 H 26 NO 4 Br, and the molecular weight is 436.36. The structural formula is: RELISTOR tablets for oral administration are film-coated and contain 150 mg of methylnaltrexone bromide (equivalent to 122.5 mg methylnaltrexone). Inactive ingredients are silicified microcrystalline cellulose, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, crospovidone, poloxamer 407, stearic acid (vegetable source), colloidal silicon dioxide, edetate calcium disodium, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc. RELISTOR for subcutaneous administration is a sterile, clear and colorless to pale yellow aqueous solution. Each 3 mL vial contains 12 mg of methylnaltrexone bromide (equivalent to 9.8 mg of methylnaltrexone) 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 (equivalent to 6.5 mg of methylnaltrexone) 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 (equivalent to 9.8 mg of methylnaltrexone) 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. chemstructure

What Is Methylnaltrexone Bromide Used For?

1 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, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. ( 1.1 ) RELISTOR injection is indicated for the treatment of OIC in adults with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care. ( 1.2 ) 1.1 Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR tablets and RELISTOR injection are indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. 1.2 Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR injection is indicated for the treatment of OIC in adult patients with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care.

Dosage and Administration

2 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: Patients receiving opioids for less than 4 weeks may be less responsive to RELISTOR. 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 ) Preparation and Administration of RELISTOR Injection ( 2.6 ) For subcutaneous use only. Inject in upper arm, abdomen or thigh. Rotate injection sites. 2.1 Important Administration Information Be within close proximity to toilet facilities once RELISTOR is administered. Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued. In adult patients with chronic non-cancer pain and OIC: Patients receiving opioids for less than 4 weeks may be less responsive to RELISTOR [see Clinical Studies ( 14.1 )]. Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days. Re-evaluate the continued need for RELISTOR when the 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. 2.2 Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The recommended dosage of RELISTOR tablets is 450 mg taken orally once daily in the morning. The recommended dosage of RELISTOR injection is 12 mg administered subcutaneously once daily. 2.3 Opioid-Induced Constipation in Adult Patients with Advanced Illness 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS Serious and important adverse reactions described elsewhere in the labeling include: Gastrointestinal perforation [see Warnings and Precautions ( 5.1 )] Severe or persistent diarrhea [see Warnings and Precautions ( 5.2 )] Opioid withdrawal [see Warnings and Precautions ( 5.3 )] The most common adverse reactions are: OIC in adult patients with chronic non-cancer pain ( 6.1 ) RELISTOR tablets (≥ 2%): abdominal pain, diarrhea, headache, abdominal distention, vomiting, hyperhidrosis, anxiety, muscle spasms, rhinorrhea, and chills. RELISTOR injection (≥ 1%): abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills. OIC in adult patients with advanced illness ( 6.1 ) RELISTOR injection (≥ 5%): abdominal pain, flatulence, nausea, dizziness, and diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain The safety of RELISTOR tablets was evaluated in a double-blind, placebo-controlled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 12-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR tablets 450 mg orally (200 patients) or placebo (201 patients) [see Clinical Studies ( 14.1 ) ] . After 4 weeks of double-blind treatment administered once daily, patients continued 8 weeks of double-blind treatment on an as needed basis (but not more than once daily). The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR tablets are shown in Table 4 . Adverse reactions of abdominal pain, diarrhea, hyperhidrosis, anxiety, rhinorrhea, and chills may reflect symptoms of opioid withdrawal. Table 4: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Tablets in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 1) 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% The safety of RELISTOR injection was evaluated in a double-blind, placebo-controlled trial in adult patients with OIC and chronic non-cancer pain receiving opioid analgesia. This study (Study 2) included a 4-week, double-blind, placebo-controlled period in which adult patients were randomized to receive RELISTOR injection 12 mg subcutaneously once daily (150 patients) or placebo (162 patients) [see Clinical Studies ( 14.1 )] . After 4 weeks of double-blind treatment, patients began an 8‑week open-label treatment period during which RELISTOR injection 12 mg subcutaneously was administered less frequently than the recommended dosage regimen of 12 mg once daily. The most common adverse reactions in adult patients with OIC and chronic non-cancer pain receiving RELISTOR injection are shown in Table 5 . The adverse reactions in the table below may reflect symptoms of opioid withdrawal. Table 5: Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR Injection in Adult Patients with OIC and Chronic Non-Cancer Pain (Study 2) Adverse Reaction RELISTOR Injection 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 at least 1% of patients receiving RELISTOR injection 12 mg subcutaneously once daily and at an incidence greater than...

Drug Interactions

7 DRUG INTERACTIONS Other Opioid Antagonists : Potential for additive effect and increased risk of opioid withdrawal; avoid concomitant use. ( 7.1 ) 7.1 Other Opioid Antagonists 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. 7.2 Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.3 mg/kg of RELISTOR did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. 7.1 Other Opioid Antagonists 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. 7.2 Drugs Metabolized by Cytochrome P450 Isozymes In healthy subjects, a subcutaneous dose of 0.3 mg/kg of RELISTOR did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

Contraindications

4 CONTRAINDICATIONS RELISTOR 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 [see Warnings and Precautions ( 5.1 )] . Patients with known or suspected mechanical gastrointestinal obstruction and at increased risk of recurrent obstruction. ( 4 , 5.1 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary The limited available data with RELISTOR in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriages. There are clinical considerations when RELISTOR is used by pregnant women [see Clinical Considerations]. In animal reproduction studies, no effects on embryofetal development were observed with the administration of intravenous methylnaltrexone bromide during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the subcutaneous maximum recommended human dose (MRHD) of 12 mg RELISTOR injection per day. The intravenous doses in rats and rabbits are about 0.5 times and 0.7 times, respectively, the oral MRHD of 450 mg/day [see Data]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier. Data Animal Data Reproduction studies have been performed with methylnaltrexone bromide administered during the period of organogenesis to rats at intravenous doses up to 25 mg/kg/day (about 20 times the subcutaneous MRHD of 12 mg/day based on body surface area), and did not cause any adverse effects on embryofetal development. In rabbits, intravenous doses of methylnaltrexone bromide up to 16 mg/kg/day (about 26 times the subcutaneous MRHD of 12 mg/day) did not show any embryofetal toxicity. The intravenous doses in rats (25 mg/kg/day) and rabbits (16 mg/kg/day) are about 0.5 and 0.7 times, respectively, the oral MRHD of 450 mg/day based on body surface area. A pre- and postnatal development study in rats...

Overdosage

10 OVERDOSAGE During clinical trials of RELISTOR administered orally and subcutaneously, one accidental case of methylnaltrexone bromide overdose was reported and no adverse events were reported as a result of the overdosage. A study of healthy subjects noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate. If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied NDC Number Pack Size Contents 65649-150-90 90-count bottle 100-mL bottle containing 90 tablets and 2 silica gel desiccant canisters. Each 150 mg film-coated tablet is white, round, biconvex, and debossed with “REL” on one side and plain on the other side. 65649-551-02 1 vial per carton One 12 mg/0.6 mL single-dose vial containing a colorless to pale yellow solution. 65649-552-04 7 pre-filled syringes per carton Seven 8 mg/0.4 mL single-dose pre-filled syringes with needle guard system containing a colorless to pale yellow solution. 65649-551-03 7 pre-filled syringes per carton Seven 12 mg/0.6 mL single-dose pre-filled syringes with needle guard system containing a colorless to pale yellow solution. 65649-551-07 1 pre-filled syringe per carton One 12 mg/0.6 mL single-dose pre-filled syringe with needle guard system containing a colorless to pale yellow solution. Storage Tablets Store at up to 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Injection Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.