oxycodone/naltrexone (Discontinued)

Brand and Other Names:Troxyca ER
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

oxycodone/naltrexone

extended-release capsule

  • 10mg/1.2mg
  • 20mg/2.4mg
  • 30mg/3.6mg
  • 40mg/4.8mg
  • 60mg/7.2mg
  • 80mg/9.6mg

Chronic Pain

Indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

To be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain

Opioid-naïve or nonopioid-tolerant patients

  • Starting dose: 10 mg/1.2 mg PO q12hr
  • Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

Dose titration

  • Individually titrate dose to provide adequate analgesia and minimal adverse effects
  • Steady-state plasma concentrations are achieved within 48 hr
  • May be up-titrated from current dose by increasing daily dose in increments of 20 mg/2.4 mg per day q2-3 days as needed based on efficacy, safety, and tolerability
  • If breakthrough pain experienced, assess need for a dosage increase or a rescue dose of an immediate-release analgesic

Opioid-tolerant patients

  • See Administration section for conversion from other PO oxycodone formulations or other opioids to Troxyca ER
  • Patients who are opioid tolerant are those receiving the following for ≥1 week
    • ≥60 mg/day PO morphine
    • ≥25 mcg/hr transdermal fentanyl
    • ≥30 mg/day PO oxycodone
    • ≥8 mg/day PO hydromorphone
    • ≥25 mg/day PO oxymorphone, OR
    • Equianalgesic dose of another opioid

Dosage Modifications

Hepatic impairment

  • Oxycodone is extensively metabolized in the liver; initiate therapy conservatively and titrate slowly
  • Naltrexone is sequestered in the capsules and is typically not released when used as directed (ie, not crushed, chewed, or dissolved); however, an increased naltrexone AUC has been observed with compensated and decompensated liver cirrhosis
  • Monitor for CNS or respiratory depression due to increased oxycodone levels and for signs of withdrawal attributed to elevated naltrexone levels

Renal impairment

  • Oxycodone elimination is reduced in renal impairment; initiate therapy conservatively and titrate slowly
  • Naltrexone is sequestered in the capsules and is typically not released when used as directed (ie, not crushed, chewed, or dissolved); however, measurable naltrexone plasma levels have been observed in some patients
  • Since naltrexone and its primary metabolite are primarily excreted in the urine, their plasma concentration may increase with renal impairment
  • Monitor for CNS or respiratory depression due to increased oxycodone levels and for signs of withdrawal attributed to elevated naltrexone levels

Dosing Considerations

Not indicated as prn analgesic

<18 years: Safety and efficacy not established

Drug is substantially excreted in the urine; cautious, conservative use is advised with use in elderly individuals

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Interactions

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            Adverse Effects

            >10%

            Nausea (14.4-20.5%)

            Constipation (3.4-14.9%)

            1-10%

            Vomiting (6.2-9%)

            Somnolence (0.7-9%)

            Headache (1.4-7.3%)

            Pruritus (2.1-6.6%)

            Dizziness (4.1-5.9%)

            Diarrhea (2.2-5.5%)

            Dry mouth (3.2%)

            Fatigue (3.2-3.4%)

            Abdominal pain (1.4-2.9%)

            Hyperhidrosis (2.4-2.7%)

            Drug withdrawal symptoms (1-2.7%)

            Muscle spasms (0.2-2.7%)

            Hot flush (1.4-2.4%)

            Back pain (1.2-2.1%)

            Edema, peripheral (0.7-2.1%)

            Arthralgia (0.7-2.1%)

            Hypoesthesia (0-2.1%)

            Oropharyngeal pain (0-2.1%)

            Insomnia (0.7-2%)

            Postmarketing Reports

            Serotonin syndrome

            Adrenal insufficiency; mostly with use exceeding 1 month

            Anaphylaxis and pharyngeal edema

            Androgen deficiency with long-term use

            Myocardial ischemia and ventricular fibrillation reported with overdose

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            Warnings

            Black Box Warnings

            Addiction, abuse, and misuse

            • Exposes patients and other users to risk of opioid addiction, abuse, and misuse, which can lead to overdose and death
            • Assess patient’s risk prior to prescribing and monitor regularly for the development of these behaviors and conditions

            Life-threatening respiratory depression

            • Serious, life-threatening, or fatal respiratory depression may occur
            • Monitor for respiratory depression, especially during initiation of, or following, a dose increase
            • Instruct patients to swallow capsules whole or to sprinkle capsule contents on applesauce and swallow immediately without chewing
            • Crushing, chewing, or dissolving can cause rapid release and absorption of a potentially fatal oxycodone dose

            Accidental ingestion

            • Accidental ingestion of even 1 dose, especially by children, can result in a fatal oxycodone overdose

            Neonatal opioid withdrawal syndrome

            • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated with management by neonatology experts
            • If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

            CYP3A4 interaction

            • Coadministration with all CYP3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and lead to respiratory depression
            • Additionally, discontinuation of concomitantly used CYP3A4 inducers may result in increased oxycodone plasma concentrations
            • Monitor closely if coadministered with CYP3A4 inhibitors or inducers
            • Also see Cautions and Drug Interactions

            Interaction with central nervous system (CNS) depressants

            • Coadministration with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
            • Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation
            • Instruct patients not to consume alcoholic beverages or use alcohol-containing drug products while taking opioid due to risk of additive sedation and respiratory depression

            Contraindications

            Patients with significant respiratory depression

            Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

            Known or suspected GI obstruction, including paralytic ileus

            Hypersensitivity (eg, anaphylaxis) to oxycodone or naltrexone or any other components of the formulation

            Cautions

            Contains oxycodone, a Schedule II controlled drug; as an opioid, oxycodone/naltrexone exposes users to the risks of addiction, abuse, and misuse; as extended-release products (eg, Troxyca ER) deliver the opioid over an extended period, there is a greater risk for overdose and death owing to the larger amount of oxycodone present (see Black Box Warnings)

            Prolonged use during pregnancy can result in neonatal withdrawal syndrome that may be fatal if not recognized and managed by neonatal experts (see Black Box Warnings)

            Adrenal insufficiency reported with opioid use (greater incidence if used >1 month); if adrenal insufficiency diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid

            Severe hypotension reported, including orthostatic hypotension and syncope in ambulatory patients; risk increases in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazine, general anesthetics); monitor for severe hypotension during dosage initiation and titration; avoid use with circulatory shock

            Oxycodone/naltrexone may further reduce respiratory drive and exacerbate CO2 retention in patients with increased ICP or brain tumors; may also obscure the clinical course in a patient with a head injury; avoid use with impaired consciousness or coma

            Contraindicated with GI obstruction (see Contraindications); oxycodone may cause spasm of the sphincter of Oddi and increase serum amylase; monitor with biliary tract disease, including acute pancreatitis, for worsening symptoms

            May increase risk of seizures; monitor with history of seizure disorders for worsened seizure control during therapy

            Altering the drug by crushing, chewing, or dissolving the pellets within the capsule can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals

            Gradually discontinue; do not stop drug abruptly (see Administration)

            May impair mental or physical abilities needed to drive or operate machinery

            Naltrexone does not interfere with thin-layer, gas-liquid, or high-pressure liquid chromatography for detection of morphine, methadone, oxycodone, or quinine in urine; naltrexone may or may not interfere with enzymatic methods for detecting opioids, depending on the sensitivity and specificity of the test

            Respiratory depression

            • Serious, life-threatening, or fatal respiratory depression has been reported with opioids, even when used as recommended; risk is greatest when initiating treatment or after increasing the dose
            • Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered drug clearance compared with younger, healthier patients
            • Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages
            • Monitor these patients closely, particularly when initiating and titrating oxycodone/naltrexone, or if coadministered with other drugs that depress respiration; alternatively, consider using nonopioid analgesics
            • Also see Black Box Warnings

            Drug interaction overview

            • CYP3A4 inhibitors and inducers
              • Oxycodone is a CYP3A4 and CYP2D6 substrate
              • Coadministration with CYP3A4 inhibitors (eg, macrolide antibiotics, azole antifungal agents, protease inhibitors) may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when a CYP3A4 inhibitor is added after a stable dose of oxycodone/naltrexone is achieved
              • Similarly, discontinuation of a CYP3A4 inducer (eg, rifampin, carbamazepine, phenytoin) in oxycodone/naltrexone-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions
              • When coadministering CYP3A4 inhibitors or discontinuing CYP3A4 inducers, monitor patients closely at frequent intervals and consider oxycodone/naltrexone dosage reduction until stable drug effects are achieved
              • These effects may be more pronounced with drugs that inhibit both CYP3A4 and CYP2D6
              • Coadministration with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone
              • When coadministering CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur
              • Also see Black Box Warnings
            • CNS depressants
              • Hypotension, profound sedation, respiratory depression, coma, and death may result if coadministered with alcohol or other CNS depressants (eg, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids)
              • Assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression
              • Also evaluate alcohol use or illicit drug use
              • If the decision to begin oxycodone/naltrexone is made, start with a lower dosage, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dose of the concomitant CNS depressant
            • Serotonergic drugs
              • Coadministration of opioids with other drugs (eg, SSRIs, SNRIs, TCAs, triptans, 5-HT3 antagonists, mirtazapine, trazodone, tramadol, MAOIs, linezolid, methylene blue) that affect the serotonergic neurotransmitter system may result in serotonin syndrome
              • If coadministration is warranted, carefully monitor, especially during treatment initiation or dose adjustment
              • Discontinue drug if serotonin syndrome suspected or evident
            • Mixed agonist/antagonists and partial agonist opioid analgesics
              • Coadministration may precipitate withdrawal
              • Avoid use with mixed agonist/antagonist (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics
            • Muscle relaxants
              • Opioids may enhance neuromuscular blockade and increase respiratory depression
              • Monitor for respiratory depression that may be more than expected with muscle relaxants; decrease dose of opioid, muscle relaxant, or both
            • Monoamine oxidase inhibitors (MAOIs)
              • Coadministration with MAOIs can potentiate oxycodone effects and increase risk of anxiety, confusion, hypotension, respiratory depression, profound sedation, coma, and death
              • Avoid concomitant use with MAOIs or within 14 days of stopping an MAOI
            • Diuretics
              • Opioids can decrease diuretic efficacy by inducing antidiuretic hormone release
              • Monitor for decreased diuresis and/or effects on blood pressure Increase diuretic dose as needed
            • Anticholinergic drugs
              • Coadministration may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus
              • Monitor for signs of urinary retention or reduced GI motility
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            Pregnancy & Lactation

            Pregnancy

            Prolonged use during pregnancy may cause neonatal opioid withdrawal syndrome (see Black Box Warnings)

            Lactation

            Oxycodone is present in breast milk; because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, breastfeeding is not recommended during treatment with oxycodone/naltrexone

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Opioid agonist/opioid antagonist combination product

            Oxycodone: Opioid agonist; relatively selective for the mu receptor, but it can bind to other opioid receptors at higher doses; inhibits ascending pain pathways, thus altering response to pain; produces analgesia, respiratory depression, and sedation

            Naltrexone: Opioid competitive receptor antagonist; shows highest affinity for mu receptors

            Absorption

            Bioavailability: 60-87% (oxycodone)

            Peak plasma time: 12 hr (oxycodone)

            Peak plasma concentration: Reduced by ~67% compared with immediate-release IR oxycodone

            AUC: Equivalent to immediate-release oxycodone

            Steady-state: Reached in 48 hr

            Crushed capsule

            • Analgesic activity primarily due to the parent drug oxycodone; oxycodone/naltrexone is designed to provide delivery of oxycodone over 12 hr
            • Chewing, crushing, or dissolving the pellets within the capsules impairs the extended-release delivery mechanism and results in the rapid release and absorption of a potentially FATAL dose of oxycodone and a potentially complete release of sequestered naltrexone
            • Peak plasma time (crushed capsule): 0.6-1 hr PO; 1.6 hr intranasal

            Distribution

            Vd: 2.6 L/kg

            Protein bound: ~45%

            Metabolism

            Oxycodone is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides

            CYP3A-mediated N-demethylation to an in active metabolite from noroxycodone is the principal metabolic pathway of oxycodone in humans

            CYP2D6-mediated O-demethylation to an active metabolite oxymorphone is a minor metabolic pathway

            Elimination

            Half-life: ~7.2 hr (oxycodone)

            Total plasma clearance: 0.8 L/min

            Urinary excretion: 19% (free oxycodone); 50% (conjugated oxycodone); ~14% (conjugated oxymorphone)

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            Administration

            Oral Administration

            Swallow capsule whole

            Instruct patients not to crush, chew, or dissolve the pellets in the capsule to avoid the risk of release and absorption of a potentially fatal dose of oxycodone and to avoid release of sequestered naltrexone that could precipitate opioid withdrawal

            Alternatively, the capsule contents (ie, pellets) may be sprinkled on a small amount of applesauce (other foods have not been tested) and swallowed immediately without chewing; rinse mouth with water and swallow to ensure all pellets have been swallowed

            Do not administer pellets through NG or G-tube

            Discontinuation

            • Do not abruptly discontinue
            • Taper the dose gradually, by 25-50% q2-4 days, while monitoring carefully for signs and symptoms of withdrawal
            • If withdrawal signs or symptoms occur, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both

            Opioid Tolerant Patients

            60 mg/7.2 mg and 80 mg/9.6 mg capsules, single doses >40 mg/4.8 mg, or a total daily dose >80 mg/9.6 mg are only for patients in whom tolerance to an opioid of comparable potency has been established

            Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals

            Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse

            Conversion from other PO oxycodone

            • Patients receiving other oral oxycodone formulations may be converted to oxycodone/naltrexone by administering 50% of the patient’s total daily PO oxycodone dose as Troxyca ER q12hr

            Conversion from other opioids

            • Discontinue all other around-the-clock opioid drugs when initiating oxycodone/naltrexone
            • When converting patients to oxycodone/naltrexone, it is safer to underestimate a patient’s 24-hr oral oxycodone requirements and provide rescue medication (eg, immediate-release opioid) than to overestimate the 24-hr oral oxycodone requirements, which could result in adverse reactions
            • Conversion factors to oxycodone
              • Codeine: 0.1
              • Hydrocodone: 0.67
              • Hydromorphone: 2.67
              • Morphine: 0.67
              • Oxycodone: 1
            • Calculate ~total daily PO oxycodone dose
              • Multiply current total daily dose of the opioid by the conversion factor listed above by appropriate conversion factor (if >1 opioid, calculate total daily for each opioid factor and add the sum totals)
              • Use only the opioid component to calculate total daily dose of combination opioid/nonopioid analgesics
              • Reduce the estimated total daily oxycodone dose by 50% to obtain the daily dose of Troxyca ER; divide this daily dose in half to obtain the q12hr dose
              • After conversion, if the total daily opioid requirement is ≤20 mg/day of oxycodone, initiate with Troxyca ER 10 mg/1.2 mg q12hr
              • Always round the dose down, if necessary, to the appropriate Troxyca ER strength
              • Provide prompt-acting rescue analgesic as needed (eg, immediate-release oxycodone)
              • Reevaluate total daily dose (scheduled plus short-acting rescue medication) to adjust dose; additionally, monitor for any signs of opioid withdrawal
            • Conversion example
              • Hydrocodone extended-release 30 mg PO q12hr = 60 mg/day
              • 60 mg hydrocodone x 0.67 (conversion factor) = oxycodone 40.2 mg/day
              • Oxycodone 40.2 mg/day reduced by 50% ~20 mg/day
              • Divided 20 mg/day in half to obtain the q12hr Troxyca ER dose; for this example, it would be 10 mg/1.2 mg PO q12hr

            Conversion from methadone

            • Close monitoring is essential when converting from methadone to other opioid agonists
            • The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure

            Conversion from transdermal fentanyl

            • May initiate oxycodone/naltrexone 18 hr after removing transdermal fentanyl patch
            • A conservative estimated dose of 10 mg/1.2 mg PO q12hr oxycodone/naltrexone should be substituted for each 25-mcg/hr fentanyl patch
            • Monitor closely during conversion; limited documented experience with this conversion

            Conversion from transdermal buprenorphine

            • There has been no systematic assessment of this conversion
            • Initiate oxycodone/naltrexone 10 mg/1.2 mg PO q12hr
            • Monitor closely during conversion; limited documented experience with this conversion

            Conversion from tramadol

            • Tramadol has both serotonergic and opioid activity, and there has been no systematic assessment of this conversion
            • Initiate oxycodone/naltrexone 10 mg/1.2 mg PO q12hr
            • Monitor closely during conversion; limited documented experience with this conversion

            Storage

            Store at 25°C (77°F); excursions permitted from 15-30°C (59-86°F)

            Dispense in tight (USP), light-resistant, child-resistant containers

            Instruct patients to take steps to store securely and dispose of unused drug by flushing the capsules down the toilet

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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.