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Oxycodone and Naltrexone

Pronunciation

(oks i KOE done & nal TREKS one)

Index Terms

  • Naltrexone and Oxycodone
  • Oxycodone Hydrochloride and Naltrexone Hydrochloride
  • Troxyca ER

Pharmacologic Category

  • Analgesic, Opioid
  • Opioid Antagonist

Pharmacology

Oxycodone: Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.

Naltrexone: Pure opioid antagonist; reverses the subjective and analgesic effects of mu-opioid receptor agonists by competitively binding at mu-opioid receptors.

Use: Labeled Indications

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

Limitations of use: Reserve oxycodone/naltrexone ER for use in patients for whom alternative treatment options (eg, nonopioid analgesics, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Oxycodone/naltrexone ER is not indicated as an as-needed ("prn") analgesic.

Contraindications

Hypersensitivity (eg, anaphylaxis) to oxycodone, naltrexone, or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected).

Dosing: Adult

Pain management: Oral: Note: Individualize treatment using the lowest effective dose for the shortest duration based on patient’s pain severity, response, prior analgesic treatment experience, and risk factors for addiction/abuse/misuse. Oxycodone 60 mg/naltrexone 7.2 mg, oxycodone 80 mg/naltrexone 9.6 mg, single doses > oxycodone 40 mg/naltrexone 4.8 mg or a total daily dose > oxycodone 80 mg/naltrexone 9.6 mg should only be used in opioid-tolerant patients. Opioid tolerance is defined as: Patients already taking at least 60 mg/day of oral morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day of oral oxycodone, 8 mg/day of oral hydromorphone, 25 mg/day of oral oxymorphone, 60 mg/day of oral hydrocodone, or an equianalgesic dose of another opioid. Patients who experience breakthrough pain may require a rescue medication with an appropriate dose of an immediate-release analgesic.

Opioid-naive or not opioid tolerant: Initial: Oxycodone 10 mg/naltrexone 1.2 mg every 12 hours.

Converting from other opioids: Monitor closely during conversion:

Currently on other oral oxycodone formulations: Administer 50% of the patient's total daily oral oxycodone dose as oxycodone/naltrexone ER every 12 hours.

Currently on other oral opioids: Discontinue all other around-the-clock opioids; convert the patient’s current total daily opioid dose(s) to an equivalent daily oxycodone dose (see manufacturer’s labeling for conversion instructions).After equivalent daily oxycodone dose is determined, reduce the estimated total daily oxycodone dose by 50% and then divide the daily dose in half to obtain the 12 hour dose of oxycodone/naltrexone ER needed. If the total daily opioid requirement is ≤20 mg, initiate therapy with oxycodone 10 mg/naltrexone 1.2 mg every 12 hours.

Currently on transdermal fentanyl: Initial: Oxycodone 10 mg/naltrexone 1.2 mg every 12 hours substituted for each 25 mcg/hour fentanyl transdermal patch beginning at least 18 hours after removal of the transdermal fentanyl patch.

Currently on transdermal buprenorphine or tramadol: Initial: Oxycodone 10 mg/naltrexone 1.2 mg every 12 hours (initiated after discontinuing the around-the-clock buprenorphine or tramadol).

Dose adjustment: Dose is individualized; titrate dose cautiously in increments of oxycodone 20 mg/naltrexone 2.4 mg every 2 to 3 days based on patient response.

Discontinuation of therapy: Dose should be gradually tapered by 25% to 50% every 2 to 4 days; do not abruptly discontinue.

Dosing: Geriatric

Refer to adult dosing. Initiate therapy at low end of dosing range; titrate dose cautiously to lowest dose that provides adequate pain relief with acceptable side effects.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; monitor closely for signs of CNS or respiratory depression due to elevated levels of oxycodone and for signs of withdrawal due to elevated levels of naltrexone and adjust dose based on clinical response.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; monitor patients closely for signs of CNS or respiratory depression due to elevated levels of oxycodone and for signs of withdrawal due to elevated levels of naltrexone and adjust dose based on clinical response.

Administration

For oral administration only; do not administer through a nasogastric or gastric tube. Swallow capsule whole; do not crush, chew, or dissolve the pellets in capsule. May sprinkle the capsule contents on applesauce and immediately swallow without chewing in patients unable to swallow capsule whole.

Storage

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

CYP3A4 Inhibitors (Strong): May enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Gastrointestinal Agents (Prokinetic): Analgesics (Opioid) may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MAO Inhibitors: OxyCODONE may enhance the serotonergic effect of MAO Inhibitors. This could result in serotonin syndrome. Management: Seek alternatives when possible. Avoid use of oxycodone/naltrexone during and within 14 days after monoamine oxidase inhibitor treatment. Non-US labeling for some oxycodone products states that such use is contraindicated. Consider therapy modification

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Analgesics (Opioid). Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy

RifAMPin: May decrease the serum concentration of OxyCODONE. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: Analgesics (Opioid) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of OxyCODONE. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Voriconazole: May enhance the adverse/toxic effect of OxyCODONE. Voriconazole may increase the serum concentration of OxyCODONE. Management: A reduced oxycodone dose may be necessary with concurrent voriconazole. Increased frequency and duration of monitoring for oxycodone-related adverse effects is recommended. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Refer to individual agents.

Adverse Reactions

Also see individual agents.

>10%: Gastrointestinal: Nausea (14%)

1% to 10%:

Cardiovascular: Peripheral edema (2%), bradycardia (<2%), chest pain (<2%), edema (<2%), increased blood pressure (<2%), palpitations (<2%), tachycardia (<2%)

Central nervous system: Dizziness (4%), drug withdrawal (3%), fatigue (3%), hypoesthesia (2%), abnormal dreams (<2%), chills (<2%), confusion (<2%), disorientation (<2%), disturbance in attention (<2%), drug abuse (<2%), irritability (<2%), lethargy (<2%), malaise (<2%), migraine (<2%), pain (<2%), paresthesia (<2%), vertigo (<2%), voice disorder (<2%)

Dermatologic: Hyperhidrosis (3%), pruritus (2%), skin rash (<2%), urticaria (<2%)

Endocrine & metabolic: Decreased libido (<2%), decreased plasma testosterone (<2%), gout (<2%), increased serum glucose (<2%)

Gastrointestinal: Diarrhea (6%), vomiting (6%), constipation (3%), decreased appetite (<2%), dysgeusia (<2%), dyspepsia (<2%)

Genitourinary: Dysuria (<2%), hematuria (<2%)

Hematologic & oncologic: Anemia (<2%), lymphadenopathy (<2%)

Hepatic: Abnormal hepatic function tests (<2%)

Hypersensitivity: Hypersensitivity reaction (<2%)

Neuromuscular & skeletal: Muscle spasm (3%), arthralgia (2%), arthritis (<2%), muscle twitching (<2%), myalgia (<2%), stiffness (<2%, musculoskeletal)

Ophthalmic: Increased lacrimation (<2%)

Otic: Tinnitus (<2%)

Respiratory: Oropharyngeal pain (3%), chronic bronchitis (<2%), dyspnea (<2%), flu-like symptoms (<2%), rhinorrhea (<2%)

Miscellaneous: Fever (<2%)

<1% (Limited to important or life-threatening): Respiratory depression

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

Oxycodone/naltrexone extended-release (ER) exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing oxycodone/naltrexone ER and monitor all patients regularly for the development of these behaviors or conditions.

Life-threatening respiratory depression:

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

Accidental ingestion:

Accidental ingestion of even one dose of oxycodone/naltrexone ER, especially by children, can result in a fatal overdose of oxycodone.

Neonatal opioid withdrawal:

Prolonged use of oxycodone/naltrexone ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed 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.

Cytochrome P450 3A4 interaction:

The concomitant use of oxycodone/naltrexone ER with all cytochrome P450 (CYP-450) 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used CYP3A4 inducer may result in an increase in oxycodone plasma concentrations. Monitor patients receiving oxycodone/naltrexone ER and any CYP3A4 inhibitor or inducer.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Constipation: Oxycodone may cause constipation which may be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration; dose adjustment may be warranted. Avoid use in patients with circulatory shock.

• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxymorphone).

• Respiratory depression: [US Boxed Warning]: May cause serious, life-threatening, or fatal respiratory depression. Monitor closely for respiratory depression, especially during initiation or dose escalation. Patients should swallow tablets whole or sprinkle the contents of the capsule on applesauce and swallow immediately without chewing; crushing, chewing, or dissolving can cause rapid release and a potentially fatal dose. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

Disease-related concerns:

• Abdominal conditions: Opioids may obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use opioids with caution in patients with adrenocortical insufficiency, including Addison disease; dose adjustment may be warranted. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use opioids with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid the use of oxycodone in patients with CNS depression or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Head trauma: Use opioids with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment; oxycodone is extensively metabolized in the liver its clearance may decrease and an increase in naltrexone AUC in patients with compensated and decompensated liver cirrhosis has been reported. Monitor patients closely for signs of CNS or respiratory depression due to elevated levels of oxycodone and for signs of withdrawal due to elevated levels of naltrexone and adjust dose based on clinical response.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).

• Obesity: Use opioids with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use opioids with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use opioids with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment; elimination of oxycodone is impaired and naltrexone plasma concentrations may be increased in patients with renal impairment. Monitor patients closely for signs of CNS or respiratory depression due to elevated levels of oxycodone and for signs of withdrawal due to elevated levels of naltrexone and adjust dose based on clinical response.

• Respiratory disease: Use opioids with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, or preexisting respiratory depression, particularly when initiating therapy and titrating; even therapeutic doses may decrease respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients.

• Seizures: Use opioids with caution in patients with a history of seizure disorders.

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Thyroid dysfunction: Use opioids with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• CNS depressants: Dose adjustment required when initiating extended release therapy in patients taking other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

• CYP450 3A4 interaction: [US Boxed Warning]: Concomitant use of oxycodone/naltrexone ER with all CYP450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used CYP450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving oxycodone/naltrexone ER and any CYP3A4 inhibitor or inducer.

• Drug-drug interactions: Potentially significant interactions may exist requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]).

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of oxycodone/naltrexone ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and requires management according to protocols developed 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 appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Other warnings/precautions:

• Abuse/misuse/diversion: [US Boxed Warning]: Oxycodone/naltrexone ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing oxycodone/naltrexone ER, and monitor all patients regularly for the development of these behaviors or conditions. Crushing, chewing, or dissolving the product can cause rapid release and absorption of a potentially fatal dose of oxycodone. Use with caution in patients with a history of drug abuse, acute alcoholism, or mental illness (eg, major depression); potential for drug dependency exists. Tolerance, psychological, and physical dependence may occur with prolonged use. Other factors associated with increased risk include younger age and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose of oxycodone/naltrexone ER, especially in children, can result in a fatal overdose of oxycodone.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).

• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postoperative patients receiving opioids. Patients interrupting therapy to undergo pain-relieving procedures (eg, chordotomy) may require a dosage adjustment when resuming therapy after the postoperative recovery period.

• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms. Do not abruptly stop oxycodone/naltrexone ER; gradually decrease dose to prevent signs and symptoms of withdrawal.

Monitoring Parameters

Pain relief; respiratory and mental status, blood pressure; constipation; signs of misuse, abuse, and addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013).

Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Pregnancy Considerations

[US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. The naltrexone component may precipitate withdrawal in the fetus. Refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, sweating a lot, loss of strength and energy, back pain, or insomnia. Have patient report immediately to prescriber difficulty breathing, slow breathing, shallow breathing, shortness of breath, angina, tachycardia, severe dizziness, passing out, severe constipation, severe abdominal pain, abdominal edema, seizures, severe fatigue, severe headache, sexual dysfunction (males), amenorrhea, decreased libido, infertility, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), or signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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