Version July 2025
Pain management: Oral:
Note: Oxycodone 5 mg/naloxone 2.5 mg tablets are intended only for use in titration or dosage adjustment. Multiple units of oxycodone 5 mg/naloxone 2.5 mg should not be substituted for other tablet strengths. Do not exceed single doses of oxycodone 40 mg/naloxone 20 mg or total daily doses of oxycodone 80 mg/naloxone 40 mg. Oxycodone 40 mg/naloxone 20 mg tablets are for use only in opioid-tolerant patients. Patients considered opioid tolerant are those already receiving opioid therapy for at least 1 week with doses exceeding 60 mg of oral morphine or its equivalent (Ref).
Opioid-naive patients: Initial dose: Oxycodone 10 mg/naloxone 5 mg every 12 hours
Opioid-experienced patients: Initial dose:
Currently on other oral oxycodone formulations: Note: Discontinue all other around-the-clock oxycodone medications prior to initiation of oxycodone/naloxone. Initiate oxycodone/naloxone at the same total daily oral oxycodone dosage, in 2 equally divided doses administered every 12 hours. Maximum single dose: Oxycodone 40 mg/naloxone 20 mg; Maximum daily dose: Oxycodone 80 mg/naloxone 40 mg/day.
Currently on other oral opioids: Discontinue all other around-the-clock opioids. Initiate oxycodone/naloxone at the lowest available strength; adequate rescue medication should be provided. Maximum single dose: Oxycodone 40 mg/naloxone 20 mg; Maximum daily dose: Oxycodone 80 mg/naloxone 40 mg/day.
Dose adjustment: Dose is individualized; titrate dose cautiously every 1 to 2 days until satisfactory response and acceptable adverse effects. Repeated pain at the end of the dosing interval may indicate the need for a dose adjustment rather than adjusting the dosing interval. Maximum single dose: Oxycodone 40 mg/naloxone 20 mg; Maximum daily dose: Oxycodone 80 mg/naloxone 40 mg/day. Note: For patients requiring higher doses of oxycodone/naloxone that exceed single or daily maximums, administration of supplemental controlled-release oxycodone at the same time intervals should be considered.
Patients requiring rescue medication: Patients who experience breakthrough pain may require a rescue medication with an appropriate dose of an immediate-release analgesic. Note: Rescue medications used in clinical trials were immediate release oxycodone or combination products containing codeine.
Administer a single dose of an immediate release opioid that is approximately 16% of the equivalent daily dose of oxycodone. Patients requiring >2 doses daily of rescue medication should have oxycodone/naloxone dose titrated upward every 1 to 2 days until satisfactory response is achieved (not to exceed recommended maximum dosing). Dosing interval (every 12 hours) should not be adjusted.
Discontinuation of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid's pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone or nalmefene. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild or moderate impairment: Reduce dose to 33% to 50% of the usual starting dose; titrate cautiously; consider use of alternative treatments without naloxone in patients with severe renal impairment.
Severe impairment: Use is contraindicated.
Mild impairment: Initial: Reduce dose to 33% to 50% of the usual starting dose; titrate cautiously.
Moderate to severe impairment: Use is contraindicated.
Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults. Also see individual agents.
1% to 10%:
Cardiovascular: Peripheral edema (2% to 5%)
Dermatologic: Hyperhidrosis (7%), skin rash (1%)
Endocrine & metabolic: Hot flash (1%), hyperglycemia (1%), hyperlipidemia (1%), hyperuricemia (1%)
Gastrointestinal: Abdominal pain (8%; lower abdominal pain [<1%]), anorexia (8%), constipation (7%), flatulence (1%), gastroenteritis (2%), nausea (8%), vomiting (7%), xerostomia (3%)
Genitourinary: Urinary tract infection (4%)
Hematologic & oncologic: Anemia (5%)
Infection: Influenza (1%), viral infection (2%)
Nervous system: Asthenia (1% to 7%), chills (1%), depression (2%), drowsiness (1%), fatigue (5%), headache (5%), migraine (1%), tremor (1%), withdrawal syndrome (8%)
Neuromuscular & skeletal: Osteoarthritis (1%)
Respiratory: Bronchitis (2%), sinusitis (1%)
<1%:
Cardiovascular: Angina pectoris, chest pain, cold extremity, ECG abnormality, first-degree atrioventricular block, hypertensive crisis, hypotension, increased blood pressure, increased heart rate, palpitations, right bundle branch block, syncope, thrombophlebitis (superficial), thrombosis
Dermatologic: Cellulitis, eczema, furuncle, night sweats, pruritic rash, pruritus, stasis dermatitis
Endocrine & metabolic: Decreased serum phosphate, hyponatremia, increased lactate dehydrogenase, increased thirst, loss of libido, weight loss
Gastrointestinal: Abdominal distention, anal fissure, anorectal pain, biliary obstruction, cholelithiasis, diverticulitis of the gastrointestinal tract (intestinal), dysgeusia, eructation, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, glossitis, mucous membrane disease, periodontitis, spasm of sphincter of Oddi
Genitourinary: Dysmenorrhea, erectile dysfunction, pollakiuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage
Hematologic & oncologic: Decreased platelet count
Hepatic: Abnormal hepatic function tests, increased liver enzymes, increased serum alanine aminotransferase, increased serum bilirubin
Hypersensitivity: Hypersensitivity reaction
Infection: Candidiasis
Local: Localized edema
Nervous system: Abnormal dreams, antisocial behavior, anxiety, balance impairment, changes in thinking, confusion, depressed mood (including negative thoughts), disorientation, disturbance in attention, euphoria, falling, hallucination, irritability, lethargy, memory impairment, nightmares, noncardiac chest pain, panic attack, paresthesia, polyneuropathy, restless leg syndrome, restless sleep, sedated state, sensation of cold, speech disturbance, stupor, tension headache, tonic-clonic seizure, yawning
Neuromuscular & skeletal: Gout, gouty arthritis, inflammatory polyarthropathy, joint swelling, lipoma, muscle rigidity, muscle spasm, muscle twitching, musculoskeletal chest pain, myalgia, state of neuromuscular blockade, tenosynovitis
Ophthalmic: Blurred vision, dry eye syndrome, increased lacrimation, photopsia, visual impairment
Otic: Deafness (unilateral), impacted cerumen, otitis externa, tinnitus
Respiratory: Cough, dyspnea, dyspnea on exertion, epistaxis, flu-like symptoms, hemoptysis, pneumonia, rhinitis
Miscellaneous: Swelling
Frequency not known:
Gastrointestinal: Diarrhea
Nervous system: Drug abuse, neonatal withdrawal, opioid dependence
Respiratory: Respiratory depression, sleep apnea (including central sleep apnea syndrome and obstructive sleep apnea syndrome)
Postmarketing:
Genitourinary: Hypogonadism (Brennan 2013; Debono 2011)
Nervous system: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023), serotonin syndrome
Hypersensitivity to oxycodone, naloxone, or any component of the formulation; moderate to severe hepatic impairment (Child-Pugh classes B and C); severe renal impairment; known or suspected GI obstruction (eg, bowel obstruction, strictures) or any disease that affects bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild, intermittent, or short duration pain that can be managed with other pain medications; management of acute pain, including use in outpatient or day surgeries; management of perioperative pain; acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus; acute respiratory depression; cor pulmonale; hypercapnia; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury; concurrent use or use within 14 days of monoamine oxidase inhibitors; opioid-dependent patients and for opioid withdrawal treatment; use in patients who are breastfeeding, pregnant, or during labor and delivery; rectal administration.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 that require mental alertness (eg, operating machinery, driving). Ethanol may enhance CNS depression; avoid use during therapy.
• Diarrhea: Naloxone may cause diarrhea; patients should be instructed to report severe or persistent diarrhea lasting >3 days.
• Hyperalgesia: Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs that 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; vasodilatory effects of oxycodone may further reduce cardiac output and worsen hypotension.
• Respiratory depression: Serious, life-threatening, or fatal respiratory depression may occur; monitor for respiratory depression, especially during initiation or following dose increase. In cases where pain suddenly subsides, respiratory depressant effects may rapidly become manifest. Careful dose titration is necessary to reduce the risk of respiratory depression. Limit use of the 40 mg/20 mg tablets to patients with established tolerance to an opioid of comparable potency (single doses >40 mg or daily doses >80 mg of oxycodone may cause fatal respiratory depression in patients who are not tolerant to the respiratory depressant effects of opioids). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
• Serotonin syndrome: Rare, but potentially life-threatening, serotonin syndrome has occurred with serotonergic agents (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors), particularly when used in combination with other serotonergic agents. Do not use in combination with monoamine oxidase inhibitors (MAOIs) or serotonin precursors (eg, l-tryptophan, oxitriptan); use with caution in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants, lithium, tramadol, St. John's wort). Discontinue treatment immediately if signs/symptoms arise.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Adrenocortical insufficiency has been reported with opioid use; usually occurs with use >1 month. Use 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 mood disorders and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction; dose adjustment may be warranted. Opioids may cause constriction of the sphincter of Oddi.
• Cardiovascular disease: Use with caution in patients with preexisting cardiovascular disease.
• Hepatic impairment: Use with caution in patients with mild hepatic impairment; dose adjustment is necessary. Use is contraindicated with moderate to severe hepatic impairment.
• 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 potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).
• Obesity: Use with caution in patients who are morbidly obese.
• Peritoneal carcinomatosis: Not indicated in patients with cancer associated with peritoneal carcinomatosis; has not been studied.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture; dose adjustment may be warranted.
• Psychosis: Use with caution in patients with toxic psychosis; dose adjustment may be warranted.
• Renal impairment: Use with caution in patients with renal impairment; dose adjustment is necessary. Use is contraindicated in severe renal impairment.
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction (eg, hypothyroidism, myxedema); dose adjustment may be warranted.
Concurrent drug therapy issues:
• Alcohol: Avoid concomitant use of alcohol with oxycodone/naloxone ER as it may result in dangerous addictive effects, resulting in serious injury or death. Patients should be instructed not to consume alcohol during treatment.
• Benzodiazepines or other CNS depressants: Concomitant use may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant therapy for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Consider prescribing naloxone or nalmefene for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.
• Monoamine oxidase inhibitors: MAOIs intensify the effects of opioids, which can cause anxiety, confusion, and decreased respiration. Concurrent use with or within 14 days of MAOIs is contraindicated.
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. Dose adjustment may be warranted. Consider the use of alternative nonopioid analgesics in these patients.
• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.
• Neonates: Neonatal withdrawal syndrome: Prolonged use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life threatening. 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.
Dosage form specific issues:
• Tablet shell: Insoluble tablet shell may remain intact and be visible in the stool.
Other warnings/precautions:
• Accidental ingestion: Accidental ingestion of even 1 dose of oxycodone/naloxone ER, especially in children, can result in a fatal overdose of oxycodone.
• Appropriate use: Rectal administration is contraindicated due to the possible increased systemic availability of naloxone by this route and potential for occurrence of severe withdrawal effects.
- Outpatient setting: Opioids should not be used as first-line therapy for acute (<1-month duration), subacute (1- to 3-month duration), or chronic pain (>3-month duration [outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment]). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants) as appropriate for the specific condition. If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks and realistic benefits of opioid therapy should be discussed with the patient. For the treatment of acute pain, therapy should only be given for the expected duration of pain severe enough to require opioids and prescribed as needed (not scheduled). For the treatment of subacute and chronic pain, 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. Risk to patients increases with higher opioid dosages. Dosages ≥50 MME/day are likely to not have increased benefit to pain relief or function relative to overall risk to patients; before increasing dosage to ≥50 MME/day, readdress pain and reassess evidence of individual benefits and risks (CDC [Dowell 2022]).
-Limitations of use: Because of the risks of substance use disorder, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with controlled release opioid formulations, oxycodone/naloxone ER should only be used in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would otherwise be inadequate to provide appropriate pain management. Not indicated as an as-needed analgesic; should not be used to treat nonopioid related constipation or for the management of substance use disorders. Patients with a history of drug or alcohol use disorder may be at increased risk of substance use disorder to oxycodone/naloxone ER.
• Naloxone/Nalmefene access: Discuss the availability of naloxone or nalmefene with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone or nalmefene to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone or nalmefene (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone or nalmefene, and getting emergency help.
• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.
• Substance use disorder/abuse/misuse: Use poses risk of opioid use disorder, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing oxycodone/naloxone ER and monitor all patients regularly for the development of these behaviors or conditions. Store securely to avoid theft or misuse. Tolerance, psychological, and physical dependence may occur with prolonged use. If abused parenterally, excipients in the tablet (eg, talc) may cause local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Marked withdrawal symptoms may occur if abused parenterally, intranasally, or rectally by those dependent on opioid agonists. Use with caution in patients with a history of substance abuse disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other CNS depressants. Consider offering naloxone or nalmefene prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).
• Surgery: Use is contraindicated for perioperative use (ie, within 24 hours before or after procedure). 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 (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Taper dose gradually when discontinuing.
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release 12 Hour, Oral:
Targin: Oxycodone 10 mg and naloxone 5 mg, Oxycodone 20 mg and naloxone 10 mg, Oxycodone 40 mg and naloxone 20 mg
Targin: Oxycodone 5 mg and naloxone 2.5 mg [contains fd&c blue #1 (brill blue) aluminum lake]
CDSA-I
Oral: Administer with or without food. Swallow tablets whole one tablet at a time; do not break, crush, cut, chew, dissolve, or split. Breaking, chewing, crushing, cutting, dissolving, or splitting ER tablets will result in uncontrolled delivery of oxycodone and can lead to overdose or death. Tablets are not indicated for rectal administration; increased risk of adverse events due to enhanced rectal absorption.
Bariatric surgery: Tablet, controlled release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Controlled-release tablets (Targin) should be swallowed whole one tablet at a time. Do not break, crush, chew, dissolve, or split as this will result in uncontrolled delivery of oxycodone that can lead to overdose or death. Nonabuse-deterrent IR tablet, capsule, and oral solution formulations of oxycodone are available. Oxycodone ER capsule contents may be taken by sprinkling the contents onto soft food (ie, applesauce, ice cream, yogurt). If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, clinicians should be advised that oral morphine has been shown to have significantly increased Cmax and decreased Tmax in the immediate (1 to 2 weeks) and long-term (6 months) period after bariatric surgery.
Note: Not approved in the United States.
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. Note: Naloxone included in the formulation for the relief of opioid-induced constipation.
OxyCODONE may be confused with HYDROcodone, OxyCONTIN, oxymorphone
Naloxone may be confused with Lanoxin, nalbuphine, naltrexone
Targin may be confused with Talwin
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (opioids, all formulations and routes of administration) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).
KIDs List: Naloxone, when used in neonates for postpartum resuscitation, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided due to risk of seizure (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents with Clinically Relevant Anticholinergic Effects: May increase adverse/toxic effects of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alvimopan: Opioid Agonists may increase adverse/toxic effects 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. Risk D: Consider Therapy Modification
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amphetamines: May increase analgesic effects of Opioid Agonists. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
Buprenorphine: May decrease therapeutic effects of Opioid Agonists. Management: Seek alternatives to buprenorphine in patients receiving pure opioid agonists. If combined in certain pain management situations (eg, surgery), monitor for symptoms of therapeutic failure/high dose requirements or opioid withdrawal symptoms. Risk D: Consider Therapy Modification
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CNS Depressants: May increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider Therapy Modification
CNS Depressants: May increase CNS depressant effects 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. Risk D: Consider Therapy Modification
CYP2D6 Inhibitors (Strong): May increase serum concentration of OxyCODONE. CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of OxyCODONE. Specifically, oxymorphone concentrations may be reduced. Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease serum concentration of OxyCODONE. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of OxyCODONE. Risk C: Monitor
CYP3A4 Inhibitors (Moderate): May increase serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase adverse/toxic effects of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Risk C: Monitor
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Desmopressin: Opioid Agonists may increase hyponatremic effects of Desmopressin. Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Diuretics: Opioid Agonists may increase adverse/toxic effects of Diuretics. Opioid Agonists may decrease therapeutic effects of Diuretics. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
Eluxadoline: Opioid Agonists may increase constipating effects of Eluxadoline. Risk X: Avoid
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Gastrointestinal Agents (Prokinetic): Opioid Agonists may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Grapefruit Juice: May increase active metabolite exposure of OxyCODONE. Specifically, concentrations of oxymorphone may be increased. Grapefruit Juice may increase serum concentration of OxyCODONE. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): May decrease therapeutic effects of Opioid Agonists. Opioid Agonists may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methylnaltrexone: May increase adverse/toxic effects of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Monoamine Oxidase Inhibitors: OxyCODONE may increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: Use of oxycodone is not recommended for patients taking MAOIs or within 14 days of MAOI discontinuation. If combined, use test doses and frequent titration of small doses while monitoring blood pressure, CNS depression, and signs of serotonin syndrome. Risk D: Consider Therapy Modification
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Naldemedine: Opioid Antagonists may increase adverse/toxic effects of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid
Nalmefene: May decrease therapeutic effects of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider Therapy Modification
Naloxegol: Opioid Antagonists may increase adverse/toxic effects of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid
Naltrexone: May decrease therapeutic effects of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid
Nefazodone: Opioid Agonists (metabolized by CYP3A4) may increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Opioid Agonists (metabolized by CYP3A4). Management: If concomitant use of opioid agonists that are metabolized by CYP3A4 and nefazodone is necessary, consider dose reduction of the opioid until stable drug effects are achieved. Monitor for increased opioid effects and serotonin syndrome/serotonin toxicity. Risk D: Consider Therapy Modification
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider Therapy Modification
Opioids (Mixed Agonist / Antagonist): May decrease analgesic effects of Opioid Agonists. 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. Risk X: Avoid
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Pegvisomant: Opioid Agonists may decrease therapeutic effects of Pegvisomant. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
PHENobarbital: May increase CNS depressant effects of OxyCODONE. PHENobarbital may decrease serum concentration of OxyCODONE. Management: Avoid use of oxycodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Primidone: May increase CNS depressant effects of OxyCODONE. Primidone may decrease serum concentration of OxyCODONE. Management: Avoid use of oxycodone and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a moderate CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ramosetron: Opioid Agonists may increase constipating effects of Ramosetron. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Samidorphan: May decrease therapeutic effects of Opioid Agonists. Risk X: Avoid
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): OxyCODONE may increase serotonergic effects of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase serum concentration of OxyCODONE. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may decrease active metabolite exposure of OxyCODONE. Specifically, oxymorphone concentrations may be reduced. Risk C: Monitor
Serotonergic Agents (High Risk): OxyCODONE may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Sincalide: Drugs that Affect Gallbladder Function may decrease therapeutic effects of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider Therapy Modification
Somatostatin Analogs: Opioid Agonists may decrease analgesic effects of Somatostatin Analogs. Opioid Agonists may increase analgesic effects of Somatostatin Analogs. Risk C: Monitor
Succinylcholine: May increase bradycardic effects of Opioid Agonists. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Tilidine: May increase therapeutic effects of Opioid Agonists. Risk X: Avoid
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan 2013).
Oxycodone and naloxone cross the placenta.
Neonatal abstinence syndrome/neonatal opioid withdrawal syndrome may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). Life-threatening respiratory depression may occur in infants exposed to oxycodone in utero. Use is contraindicated during pregnancy and during labor and delivery.
Refer to individual monographs for additional information.
Oxycodone is present in breast milk; it is not known if naloxone is present in breast milk.
Infants exposed to oxycodone via breast milk are at risk for life-threatening respiratory depression. Use is contraindicated in patients who are breastfeeding. Refer to individual monographs for additional information.
Pain relief, respiratory and mental status, blood pressure; bowel function; signs/symptoms of misuse, abuse, and substance use disorder; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)
Subacute or chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). 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) (CDC [Dowell 2022]).
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; also binds to opiate receptors in peripheral organs including the gut to induce constipation.
Naloxone: Pure opioid antagonist that competes and displaces opioids at opioid receptor sites, including gut opioid receptors, which counteracts opioid-induced constipation.
Note: Compared to controlled release oxycodone, improved bowel function and similar efficacy in terms of pain relief have been observed with a controlled release formulation of oxycodone/naloxone (Ahmedzai 2012; Löwenstein 2010; Vondrackova 2008).
Note: Pharmacokinetic parameters observed with oxycodone/naloxone controlled release formulation were similar to those observed with separate administration of controlled-release formulations of each agent (Smith 2008).
Naloxone:
Bioavailability: Oral: <3%
Metabolism: Primarily hepatic via glucuronidation
Excretion: Urine (as metabolites)
Oxycodone (controlled release):
Duration: ≤12 hours
Distribution: Vd: 2.6 L/kg; distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain (Oxycontin US product labeling 2016)
Protein binding: ~45%
Metabolism: In the gut and liver to noroxycodone (via CYP3A4), oxymorphone (via CYP2D6), and noroxymorphone (via CYP2D6, CYP3A4); metabolites undergo glucuronidation. Analgesic activity of metabolites may be of little clinical significance.
Bioavailability: Up to 87% (Note: Proportional bioavailability of oxycodone 5 mg/naloxone 2.5 mg tablets to other tablet strengths has not been established.)
Half-life elimination: 4.5 hours (Oxycontin US product labeling 2016)
Time to peak, plasma: ~4 to 5 hours (Oxycontin US product labeling 2016)
Excretion: Urine and feces (as parent drug and metabolites)
Altered kidney function:
Oxycodone: For patients with mild, moderate, and severe renal impairment, the mean increase in oxycodone AUC was approximately 53%, 66%, and 124%, respectively, and the mean increase in oxycodone Cmax was approximately 10%, 35%, and 67%, respectively.
Naloxone: For patients with mild, moderate, and severe renal impairment, the mean increase in naloxone AUC was approximately 2,750%, 3,810%, and 7,512% and the mean increase in naloxone Cmax was approximately 976%, 758%, and 1,575%, respectively.
Hepatic function impairment:
Oxycodone: For patients with mild, moderate, and severe hepatic impairment, the mean increase in oxycodone AUC was approximately 43%, 219%, and 210% and Cmax was approximately 20%, 101%, and 91%, respectively.
Naloxone: For patients with mild, moderate, and severe hepatic impairment, the mean increase in naloxone AUC was approximately 311%, 11,418%, and 10,566% and the mean increase in naloxone Cmax was approximately 93%, 5,192%, and 5,152%, respectively.
