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    Peripheral Mu Opioid Receptor Antagonists for Constipation
    Peripheral Opioid Receptor Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Peripherally-acting mu-opioid receptor antagonist
    Used to treat opioid-induced constipation (OIC) in patients with advanced disease (e.g., cancer), as well as for OIC due to treatment of chronic non-cancer pain.
    Does not reverse centrally-mediated analgesia or opioid-induced respiratory depression.

    COMMON BRAND NAMES

    Relistor

    HOW SUPPLIED

    Relistor Oral Tab: 150mg
    Relistor Subcutaneous Inj Sol: 0.4mL, 0.6mL, 8mg, 12mg

    DOSAGE & INDICATIONS

    For the treatment of opiate agonist-induced constipation (OIC) in patients with advanced illness or pain caused by active cancer who require opioid dosage escalation for palliative care, and also for the treatment of OIC in patients taking opioids for 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).
    Subcutaneous dosage
    Adults with advanced illness and opioid-induced constipation weighing more than 114 kg

    0.15 mg/kg subcutaneously every other day as needed. Max: 0.15 mg/kg per 24 hours. Methylnaltrexone use for longer than 4 months in this population has not been studied.

    Adults with advanced illness and opioid-induced constipation weighing 62 to 114 kg

    12 mg subcutaneously every other day as needed. Max: 12 mg SC per 24 hours. Methylnaltrexone use for longer than 4 months in this population has not been studied.

    Adults with advanced illness and opioid-induced constipation weighing 38 to 61 kg

    8 mg subcutaneously every other day as needed. Max: 8 mg subcutaneously per 24 hours. Methylnaltrexone use for longer than 4 months in this population has not been studied.

    Adults with advanced illness and opioid-induced constipation weighing less than 38 kg

    0.15 mg/kg subcutaneously every other day as needed. Max: 0.15 mg/kg per 24 hours. Methylnaltrexone use for longer than 4 months in this population has not been studied.

    Adults with chronic non-cancer pain and opioid-induced constipation

    12 mg subcutaneously once daily. Methylnaltrexone has been shown to be efficacious in patients who have taken opioids for at least 4 weeks; sustained exposure to opioids prior to initiating methylnaltrexone may increase the patient’s sensitivity to the effects of methylnaltrexone. Discontinue all maintenance laxative therapy prior to initiation of methylnaltrexone; if response to methylnaltrexone is suboptimal after 3 days, laxative(s) can be used as needed. Re-assess the continued need for methylnaltrexone when the opioid regimen is changed to avoid adverse reactions.

    Oral dosage
    Adults with chronic non-cancer pain and opioid-induced constipation

    450 mg PO once daily in the morning. Take on an empty stomach at least 30 minutes before the first meal of the day. Methylnaltrexone has been shown to be efficacious in patients who have taken opioids for at least 4 weeks; sustained exposure to opioids prior to initiating methylnaltrexone may increase the patient’s sensitivity to the effects of methylnaltrexone. Discontinue all maintenance laxative therapy prior to initiation of methylnaltrexone; if response to methylnaltrexone is suboptimal after 3 days, laxative(s) can be used as needed. Re-assess the continued need for methylnaltrexone when the opioid regimen is changed to avoid adverse reactions.

    For the management of nausea/vomiting† related to morphine.
    Oral dosage†
    Adults

    19.2 mg/kg PO 20 minutes before morphine (0.05 mg/kg IV given over 1 minute) led to significantly less nausea as compared with placebo. Among methylnaltrexone recipients, nausea severity 3 minutes after morphine was similar to the severity before morphine receipt. Patients rated nausea on a scale from 0 (none) to 4 (extreme).

    For the treatment of pruritus† related to morphine.
    Oral dosage†
    Adults

    19.2 mg/kg PO 20 minutes before morphine (0.05 mg/kg IV given over 1 minute) led to significantly less skin itch and flushing as compared with placebo. Among methylnaltrexone recipients, skin itch and flushing severity 3 minutes after morphine was similar to the severity before morphine receipt. Patients rated skin itch and flushing on a scale from 0 (none) to 4 (extreme).

    For the management of urinary retention† from opioids.
    Intravenous dosage† (intravenous dosage is investigational)
    Adults

    0.3 mg/kg IV led to voiding in 5 of 12 sessions whereas naloxone (0.01 mg/kg IV) led to voiding in 7 of 7 sessions, and placebo led to voiding in 0 of 6 sessions. Of patients receiving remifentanil 0.15 mcg/kg/min IV, complete urinary retention occurred in 18 of 25 sessions and decreased detrusor pressure occurred in 21 of 25 sessions.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    -In patients with advanced illness and opioid-induced constipation:
    < 38 kg: 0.15 mg/kg/day subcutaneously.
    38 to < 62 kg: 8 mg/day subcutaneously.
    62—114 kg: 12 mg/day subcutaneously.
    > 114 kg: 0.15 mg/kg/day subcutaneously.
    -In patients with chronic non-cancer pain and opioid-induced constipation:
    12 mg/day subcutaneously; 450 mg/day PO.

    Geriatric

    -In patients with advanced illness and opioid-induced constipation:
    < 38 kg: 0.15 mg/kg/day subcutaneously.
    38 to < 62 kg: 8 mg/day subcutaneously.
    62—114 kg: 12 mg/day subcutaneously.
    > 114 kg: 0.15 mg/kg/day subcutaneously.
    -In patients with chronic non-cancer pain and opioid-induced constipation:
    12 mg/day subcutaneously; 450 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Child-Pugh A: No dose adjustment is required. 
    Child-Pugh B: Reduce the oral dose to 150 mg PO once daily. No dose adjustment is required for the injectable formulation.
    Child-Pugh C: Reduce the oral dose to 150 mg PO once daily. Use of the injectable formulation has not been studied in patients with severe hepatic impairment. If considering use of the injectable formulation in patients with severe hepatic impairment, reduce the dose as follows: less than 38 kg give 0.075 mg/kg subcutaneously; 38 to 61 kg give 4 mg subcutaneously; 62 to 114 kg give 6 mg subcutaneously; more than 114 kg give 0.075 mg/kg subcutaneously.

    Renal Impairment

    Patients with chronic non-cancer pain:
    CrCl > 60 mL/min: No dosage adjustment needed.
    CrCl < 60 mL/min: Reduce dose to 150 mg PO once daily or 6 mg subcutaneously once daily.
     
    Patients with advanced illness:
    CrCl > 60 mL/min: No dosage adjustment needed.
    CrCl < 60 mL/min: Reduce the normal adult weight-based subcutaneous dose by 50%. Prefilled syringes are designed to deliver a fixed dose; therefore, patients with moderate to severe renal impairment should not use the prefilled syringes unless their reduced dose is 8 mg or 12 mg.

    ADMINISTRATION

    Oral Administration

    Take on an empty stomach, at least 30 minutes before the first meal of the day.

    Injectable Administration

    Inspect the solution before use; it should be a clear and colorless to pale yellow aqueous solution. Do not use if particulate matter or discoloration are present.
    Administer as a subcutaneous injection only.

    Subcutaneous Administration

    Administer by subcutaneous injection into the upper arm, abdomen, or thigh no more than once every 24 hours.
    The upper arm should not be used for self-injection.
    Rotate injection sites; do not inject the exact same spot each time. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid areas with scars or stretch marks.
     
    Single-use injection solution vials:
    A dose from the single-use vial should be administered with a 27 gauge x ½-inch needle and 1 ml syringe.
    Instruct patient on proper injection preparation and administration.
    Withdraw the needed amount of solution for the patient's weight-based dose into the sterile syringe. If immediate administration to the patient is impossible, the syringe may be kept at room temperature for up to 24 hours. The syringe does not need to be kept away from light during the 24-hour period. Immediately discard any unused portion in the vial; no preservatives are present.
    If using a retractable needle (e.g., VanishPoint needle), slowly push down on the plunger past the resistance point until the syringe is empty and you hear a click.
    Properly dispose of the used syringe and needle.
     
    Pre-filled syringes:
    Only a patient requiring an 8 mg/0.4 ml or 12 mg/0.6 ml dose should be prescribed the pre-filled syringes. The pre-filled syringes contain fixed doses that are not to be split.
    Do not remove the pre-filled syringe from the tray until ready to administer. Protect from light until ready to use.
    Instruct patient on the proper preparation of the prefilled syringe, the injection site, and instruct regarding proper injection technique.
    Use one hand to firmly hold the barrel of the pre-filled syringe. Use the other hand to pull the needle cap straight off. Do not touch the needle or allow it to touch anything.
    Use one hand to pinch the skin around the injection site.
    Use ther other hand to hold the pre-filled syringe. Insert the full length of the needle into the skin at a 45-degree angle with a quick dart-like motion.
    Let go of the skin and slowly push the plunger in with your thumb until the pre-filled syringe is empty. This will release the needle guard (safety device).
    Continue to hold pressure on the plunger with your thumb and quickly pull the needle out of the skin. Be careful to keep the needle at the same angle as it was inserted. Remove your thumb from the plunger to allow the protective sleeve to cover the needle.
    There may be a little bleeding at the injection site. Hold a cotton ball or gauze over the injection site. Do not rub the injection site. Apply an adhesive bandage to the injection site if needed.
    Properly dispose of the used pre-filled syringe and needle.

    STORAGE

    Relistor:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    GI obstruction

    Methylnaltrexone is contraindicated in patients with known or suspected mechanical GI obstruction and patients at increased risk of recurrent GI obstruction, due to the potential for gastrointestinal perforation.

    Diarrhea

    Discontinue methylnaltrexone if severe or persistent diarrhea occurs during treatment. Methylnaltrexone is used on an as-needed basis no more frequently than once every 24 hours to treat opioid-induced constipation if laxative use has been insufficient. Instruct patients to stop methylnaltrexone if they stop opioid-agonist therapy.

    Children, infants, neonates

     Safety and efficacy of methylnaltrexone have not been established in pediatric patients (i.e., neonates, infants, children, and adolescents).

    Intravenous administration

    Do not administer methylnaltrexone by intravenous administration. The injectable formulation is only FDA approved for subcutaneous administration.

    Geriatric, renal disease, renal impairment

    Methylnaltrexone dosage adjustment is needed for patients with moderate to severe renal impairment, defined as a creatinine clearance less than 60 mL/minute. Cautious use in patients with renal disease and in geriatric patients is advised, as reduced renal function may result in elevated systemic drug exposure.

    Hepatic disease

    The oral formulation of methylnaltrexone under goes first-pass hepatic metabolism prior to reaching systemic circulation. In patients with hepatic disease, drug exposure may be increased up to 2.1-fold; thus, dosage adjustments are required for the oral formulation in patients with moderate to severe hepatic impairment (Child-Pugh B and C). The effect of severe hepatic disease on the pharmacokinetics of the injectable formulation has not been studied. Dose reductions are advised if considering use of injectable methylnaltrexone in patients with severe hepatic impairment.

    Pregnancy

    Data are limited regarding use of methylnaltrexone during pregnancy, and the drugs potential to cause birth defects or miscarriages is unknown. In animal studies, no adverse effects on embryo-fetal development were observed with administration of supratherapeutic doses. Health care providers are encouraged to consider the possibility of inducing fetal opioid withdrawal, as the immature fetal blood brain barrier may allow passage of the drug into the CNS. Prior to use, advise pregnant women of the potential for adverse fetal effects.

    Breast-feeding

    According to the manufacturer, cautious use of methylnaltrexone is advised for a woman who is breast-feeding her infant because many drugs are excreted in human milk. Methylnaltrexone excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Crohn's disease, GI perforation, neoplastic disease, peptic ulcer disease, ulcerative colitis

    Use methylnaltrexone with caution in patients with known or suspected lesions of the gastrointestinal (GI) tract and/or low GI wall integrity (e.g., those with neoplastic disease, peptic ulcer disease, Crohn's disease, Ogilvie's syndrome, ulcerative colitis), as these patients may be at increased risk of developing GI perforation. Patients with advanced forms of these illnesses have suffered GI perforation involving the stomach, duodenum, colon, and other parts of the GI tract while receiving methylnaltrexone. Advise all patients to report severe, persistent, and/or worsening abdominal symptoms.

    Acute opioid withdrawal

    Methylnaltrexone is an antagonist of opioid binding at the mu-opioid receptor. When administered at recommended doses, methylnaltrexone functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract; the ability of methylnaltrexone to cross the blood-brain barrier is restricted. Nevertheless, symptoms consistent with acute opioid withdrawal (e.g., hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning) have occurred in patients treated with methylnaltrexone. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using methylnaltrexone in such patients; monitor for symptoms of opioid withdrawal.

    ADVERSE REACTIONS

    Severe

    GI perforation / Delayed / Incidence not known

    Moderate

    withdrawal / Early / Incidence not known

    Mild

    abdominal pain / Early / 14.0-29.0
    flatulence / Early / 13.0-13.0
    diarrhea / Early / 5.0-12.0
    nausea / Early / 9.0-12.0
    vomiting / Early / 3.0-7.0
    dizziness / Early / 7.0-7.0
    hyperhidrosis / Delayed / 3.0-6.0
    headache / Early / 4.0-4.0
    tremor / Early / 1.0-3.0
    flushing / Rapid / 3.0-3.0
    anxiety / Delayed / 2.0-2.0
    rhinorrhea / Early / 2.0-2.0
    chills / Rapid / 1.0-2.0
    malaise / Early / Incidence not known
    diaphoresis / Early / Incidence not known

    DRUG INTERACTIONS

    Alvimopan: (Major) Avoid coadministration of methylnaltrexone and other opiate antagonists, like alvimopan. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Buprenorphine; Naloxone: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Bupropion; Naltrexone: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Naldemedine: (Major) Avoid coadministration of methylnaltrexone and other opiate antagonists, like naldemedine. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Nalmefene: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Naloxegol: (Major) Avoid coadministration of methylnaltrexone and other opiate antagonists, like naloxegol. There is a potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal with concomitant use.
    Naloxone: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Naltrexone: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Olanzapine; Samidorphan: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
    Pentazocine; Naloxone: (Major) Avoid concomitant use of methylnaltrexone with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

    PREGNANCY AND LACTATION

    Pregnancy

    Data are limited regarding use of methylnaltrexone during pregnancy, and the drugs potential to cause birth defects or miscarriages is unknown. In animal studies, no adverse effects on embryo-fetal development were observed with administration of supratherapeutic doses. Health care providers are encouraged to consider the possibility of inducing fetal opioid withdrawal, as the immature fetal blood brain barrier may allow passage of the drug into the CNS. Prior to use, advise pregnant women of the potential for adverse fetal effects.

    According to the manufacturer, cautious use of methylnaltrexone is advised for a woman who is breast-feeding her infant because many drugs are excreted in human milk. Methylnaltrexone excretion into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Methylnaltrexone is a peripheral mu-opioid receptor antagonist that reduces the oral-cecal transit prolongation associated with opiate agonists. Administration of methylnaltrexone 0.1 mg/kg SC plus morphine 0.05 mg/kg IV to 6 healthy adults led to a mean oral-cecal transit time of 110 +/- 41 minutes as compared with a baseline time of 85 +/- 20.5 minutes and 155 +/- 27.9 minutes after morphine alone. Similar results were obtained after a methylnaltrexone dose of 0.3 mg/kg SC; the mean transit time was 98 +/- 49.1 minutes at baseline, 140 +/- 58.2 minutes after morphine, and 108 +/- 59.6 minutes after both morphine and methylnaltrexone. In vitro, methylnaltrexone had a positive intrinsic activity at mu opioid receptors that was consistent with partial agonism. In morphine-naive guinea pig ileum, methylnaltrexone reduced the amplitude of electrically evoked contractions and spontaneous mechanical activity, but in tissue from morphine-dependent animals, methylnaltrexone increased spontaneous activity.
     
    In addition to improved oral-cecal transit time, a reduction in opioid-induced emesis may occur with methylnaltrexone. The chemoreceptor trigger zone is physiologically located outside the blood-brain barrier, and opioid receptors in the chemoreceptor trigger zone induce emesis. Also, inhibition of gut mobility by opioids may contribute to nausea and vomiting.
     
    Peripheral mu-opioid receptor antagonism may have some utility for reducing opioid-induced urinary retention (see Dosage). After an intravenous infusion of remifentanil 0.15 mcg/kg/minute, voiding was possible in 5 of 12 patients after a single intravenous dose of methylnaltrexone 0.3 mg/kg and in none of the 6 patients who got a saline placebo. At least some of the urodynamic effects of remifentanil appear to be due to a peripheral action because none of the methylnaltrexone recipients had reversal of opioid-induced miosis. In contrast, naloxone administration reversed opioid-induced miosis and caused urinary voiding in all 7 patients.
     
    In addition to not reversing opioid-induced miosis, methylnaltrexone does not reverse opioid-induced respiratory depression. Respiratory depression due to morphine was reversed 20 minutes after naloxone 5 mcg/kg but not after methylnaltrexone 0.3 mg/kg administration or placebo administration.
     
    Lastly, methylnaltrexone does not reverse analgesia afforded by opiates or cause withdrawal symptoms among most opioid-dependent patients. In a clinical trial, methylnaltrexone 0.15 mg/kg SC did not alter pain severity or cause opioid withdrawal symptoms among patients with chronic pain and opioid-induced constipation. Nevertheless, symptoms consistent with acute opioid withdrawal (e.g., hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning) have occurred in patients treated with methylnaltrexone. Patients having disruptions to the blood-brain barrier may be at increased risk for such effects.

    PHARMACOKINETICS

    Methylnaltrexone is administered via oral and subcutaneous routes. Once in systemic circulation,  only 11 to 15.3% of the drugs is bound to plasma proteins, and the volume of distribution at steady state is 1.1 L/kg. Due to the polarity of methylnaltrexone, diffusion cross the blood-brain barrier is restricted. Instead the drug distributes and binds to peripheral mu-receptors in tissues such as the gastrointestinal tract. Methylnaltrexone is metabolized to 5 distinct metabolites through conjugation by sulfotransferase to a weak mu-receptor antagonist (i.e., methylnaltrexone sulfate) and by aldo-keto reductase 1C enzymes to active mu-receptor antagonists (i.e., methyl-6-naltrexol isomers); non-significant amounts of naltrexone are produced during N-demethylation of methylnaltrexone. Methylnaltrexone is eliminated primarily as the unchanged drug. About half of a dose is excreted in the urine, and 17% is eliminated in the feces by 168 hours post-dose. Renal excretion is 4- to 5-fold higher than creatinine clearance, suggesting the drug undergoes active renal excretion. The terminal half-life is approximately 15 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none
    In vitro, methylnaltrexone did not significantly inhibit or induce the activity of cytochrome P450 (CYP) isozymes 1A2, 2A6, 2B6, 2C9, 2C19, or 3A4. Methylnaltrexone was a weak inhibitor of CYP2D6, but in vivo, methylnaltrexone 0.3 mg/kg SC did not significantly affect the metabolism of the CYP2D6 substrate, dextromethorphan. In addition, clinically significant drug-drug interactions are not expected during inhibition of the following drug transporters: P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Protein 2 (MRP2), Organic Anion-Transporting Polypeptide (OATP1B1/1B3), Organic Cation Transporter (OCT1/2), Organic Anion Transporter (OAT1/3), Multidrug and Toxic Extrusion Transporter (MATE1/2-K).

    Oral Route

    Absolute oral bioavailability of methylnaltrexone has not been determined; however, a dose escalation study found peak drug concentrations (Cmax) and drug exposures (AUC) increase in a dose proportional manner over a dosage range of 150 to 450 mg. In health subjects receiving a single 450 mg oral dose, the time to reach maximum plasma concentration (Tmax) was approximately 1.5 hours, the mean Cmax was 48.1 ng/mL, and the mean AUC was 382 ng x hr/mL. When this dose was administration with a high-fat meal (800 to 100 kcal; 60% fat) the Cmax decreased by 60%, the AUC decreased by 43%, and the Tmax was delayed by 2 hours. Patients with opioid-induced constipation (OIC) who received a single 450 mg oral dose, achieved AUCs that were 27% lower then those observed in healthy subjects. Significant drug accumulation was not observed when a 450 mg oral dose was administered once daily for 7 days.

    Subcutaneous Route

    Peak methylnaltrexone concentrations are obtained in about 30 minutes. Both peak (Cmax) and systemic (AUC) concentrations increase in a dose-proportional manner. The mean Cmax was 117 ng/mL after a 0.15 mg/kg SC dose and 140 ng/mL after a 12 mg SC dose. The mean AUC24 was 175 ng x hr/mL after a 0.15 mg/kg SC dose and 218 ng x hr/mL after a 12 mg SC dose.