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Oxycodone and naloxone (United States: Not available): Drug information

Oxycodone and naloxone (United States: Not available): Drug information
(For additional information see "Oxycodone and naloxone (United States: Not available): Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: Canada
  • Targin
Pharmacologic Category
  • Analgesic, Opioid;
  • Opioid Antagonist
Dosing: Adult
Pain management

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 (American Pain Society 2016).

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 discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal universal tapering schedule for all patients has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Tapering schedules should be individualized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered. An even slower taper may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). 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 withdrawal symptoms (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2018).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

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.

Dosing: Hepatic Impairment: Adult

Mild impairment: Initial: Reduce dose to 33% to 50% of the usual starting dose; titrate cautiously.

Moderate to severe impairment: Use is contraindicated.

Dosing: Older Adult

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.

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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]

Controlled Substance

CDSA-I

Administration: Adult

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.

Use: Labeled Indications

Note: Not approved in the US.

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.

Medication Safety Issues
Sound-alike/look-alike issues:

OxyCODONE may be confused with HYDROcodone, OxyCONTIN, oxymorphone

Naloxone may be confused with Lanoxin, nalbuphine, naltrexone

Targin may be confused with Talwin

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Pediatric patients: High-risk medication:

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]).

Other safety concerns:

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.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%: Hematologic & oncologic: Cancer pain (12%)

1% to 10%:

Cardiovascular: Peripheral edema (2% to 5%)

Dermatologic: Pruritus (1%), skin rash (1%)

Endocrine & metabolic: Hot flash (1%), hyperglycemia (1%), hyperlipidemia (1%), hyperuricemia (1%)

Gastrointestinal: Abdominal pain (8%), anorexia (8%), constipation (7%), flatulence (1%), gastroenteritis (2%), nausea (8%), vomiting (7%), xerostomia (3%)

Genitourinary: Urinary tract infection (4%)

Hematologic & oncologic: Anemia (5%), progression of cancer (9%)

Infection: Influenza (1%), viral infection (2%)

Nervous system: Chills (1%), depression (2%), drowsiness (1%), fatigue (5%), headache (5%), migraine (1%), pain (3%), sciatica (2%), tremor (1%), withdrawal syndrome (8%)

Neuromuscular & skeletal: Asthenia (1% to 7%), back pain (3%), limb pain (2%), osteoarthritis (1%)

Respiratory: Bronchitis (2%), sinusitis (1%)

<1%:

Cardiovascular: Angina pectoris, chest pain, cold extremities, 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, minor skin lacerations, night sweats, pruritic rash, stasis dermatitis

Endocrine & metabolic: Decreased serum phosphate, gout, gouty arthritis, 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

Genitourinary: Dysmenorrhea, erectile dysfunction, pollakiuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage

Hematologic & oncologic: Decreased platelet count, lipoma

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, abnormality in thinking, antisocial behavior, anxiety, balance impairment, confusion, depressed mood (including negative thoughts), disorientation, disturbance in attention, drug dependence, euphoria, falling, hallucination, irritability, lethargy, memory impairment, nightmares, noncardiac chest pain, panic attack, paresthesia, polyneuropathy, restless leg syndrome, restless sleep, sedated state, seizure (tonic-clonic), sensation of cold, speech disturbance, stupor, tension headache, yawning

Neuromuscular & skeletal: Joint injury (sprain), joint swelling, muscle rigidity, muscle spasm, muscle strain, muscle twitching, musculoskeletal chest pain, myalgia, neck pain, polyarthralgia, shoulder pain, state of neuromuscular blockade, tenosynovitis

Ophthalmic: Blurred vision, dry eye syndrome, increased lacrimation, photopsia, visual impairment

Otic: Deafness (unilateral), impacted cerumen, otitis externa, tinnitus

Renal: Renal pain

Respiratory: Cough, dyspnea, dyspnea on exertion, epistaxis, flu-like symptoms, hemoptysis, pneumonia, respiratory depression, rhinitis

Miscellaneous: Drug overdose, drug toxicity, swelling

Frequency not known:

Dermatologic: Hyperhidrosis

Gastrointestinal: Diarrhea

Nervous system: Drug abuse, neonatal withdrawal, opioid dependence

Respiratory: Obstructive sleep apnea syndrome

Postmarketing:

Genitourinary: Hypogonadism (Brennan 2013; Debono 2011)

Nervous system: Serotonin syndrome

Contraindications

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 women who are breastfeeding, pregnant, or during labor and delivery; rectal administration.

Documentation of allergenic cross-reactivity for opioids is limited; however, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

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 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: May occur rarely with high doses of oxycodone; dose reduction or alternative opioid may be necessary.

• 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: [Canadian Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur with use of oxycodone/naloxone ER. Monitor closely for respiratory depression, especially during initiation of therapy or following a dose increase. Tablets must be swallowed whole; tablets that are broken, crushed, chewed, or dissolved may result in a rapid release and absorption of a potentially fatal dose of oxycodone. Patients should be instructed that opioid use is associated with hazards, including fatal overdose. 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 increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2016]).

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

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction (eg, hypothyroidism, myxedema); dose adjustment may be warranted.

Concurrent drug therapy issues:

• Alcohol: [Canadian Boxed Warning]: 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: [Canadian Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of oxycodone/naloxone extended release and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.

• Monoamine oxidase inhibitors: [Canadian Boxed Warning]: 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 with caution in older adult patients; may be more sensitive to adverse effects, such as respiratory depression. Oxycodone clearance may also be slightly reduced in older adult patients. Dose adjustment may be warranted. 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 (CDC [Dowell 2016]). Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: [Canadian Boxed Warning]: 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:

• Addiction/abuse/misuse: [Canadian Boxed Warning]: Use 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/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 drug or ethanol abuse or with mental illness (eg, major depression); potential for drug dependency exists. 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 [MME]/day orally), and concomitant benzodiazepine use (CDC [Dowell 2016]).

• Accidental ingestion: [Canadian Boxed Warning]: 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.

- Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment) 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, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications 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 IR opioids (instead of ER/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be reevaluated when increasing dosage to ≥50 MME/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (CDC [Dowell 2016]).

-Limitations of use [Canadian Boxed Warning]: Due to the risks of addiction, 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 addictive disorders. Patients with a history of addiction to drugs or alcohol may be at increased risk of addiction to oxycodone/naloxone ER.

• Naloxone access: Discuss the availability of naloxone 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 a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone 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 (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, 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.

• 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.

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alvimopan: Opioid Agonists 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. Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

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

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: 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. Risk D: Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of OxyCODONE. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of OxyCODONE. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Risk C: 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. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect 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 enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect 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 enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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 the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

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

HydrOXYzine: May enhance the CNS depressant effect 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

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect 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

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect 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 enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: OxyCODONE may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination

Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination

Nalmefene: May diminish the therapeutic effect 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 enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

Nefazodone: Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the 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

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect 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 combination

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

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

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

PHENobarbital: May enhance the CNS depressant effect of OxyCODONE. PHENobarbital may decrease the serum concentration of OxyCODONE. Management: Avoid use of oxycodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

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

Primidone: May enhance the CNS depressant effect of OxyCODONE. Primidone may decrease the serum concentration of OxyCODONE. Management: Avoid use of oxycodone and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased oxycodone efficacy and withdrawal if combined. Risk D: Consider therapy modification

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

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

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

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4) may enhance the serotonergic effect 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 therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect 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 diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: 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. Risk D: Consider therapy modification

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

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women (Brennan 2013).

Pregnancy Considerations

Use is contraindicated during pregnancy and during labor and delivery.

[Canadian Boxed Warning]: Infants exposed to oxycodone in utero are at risk of life-threatening respiratory depression. Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening.

Refer to individual monographs for additional information.

Breastfeeding Considerations

Use is contraindicated in breastfeeding women.

Oxycodone is present in breast milk; it is not known if naloxone is excreted in breast milk. [Canadian Boxed Warning]: Infants exposed to oxycodone through breast milk are at risk of life-threatening respiratory depression.

Refer to individual monographs for additional information.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; bowel function; signs/symptoms 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-based opioid use disorder treatment): 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). (CDC [Dowell 2016]).

Mechanism of Action

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).

Pharmacokinetics

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)

Pharmacokinetics: Additional Considerations

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.

Brand Names: International
  • Targin (AT, AU, BG, CH, CZ, DE, DK, ES, HK, IE, IL, IS, MY, PH, PL, PT, RO, SG, SK);
  • Targin PR (KR);
  • Targinact (BE, CY, EE, GB, HR, HU, LB, LU, NL, SI, TR);
  • Targiniq (FI, NO, SE)


For country code abbreviations (show table)
  1. Ahmedzai SH, Nauck F, Bar-Sela G, et al, “A Randomized, Double-Blind, Active-Controlled, Double-Dummy, Parallel-Group Study to Determine the Safety and Efficacy of Oxycodone/Naloxone Prolonged-Release Tablets in Patients With Moderate/Severe, Chronic Cancer Pain,” Palliat Med, 2012, 26(1):50-60. [PubMed 21937568]
  2. American Pain Society; Chicago, IL. Principles of Analgesic Use; 7th Edition 2016; page 38
  3. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2015;90(6):828-842. doi: 10.1016/j.mayocp.2015.04.003. [PubMed 26046416]
  4. Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3)(suppl 1):S12-S18. doi:10.1016/j.amjmed.2012.12.001. [PubMed 23414717]
  5. Centers for Disease Control and Prevention (CDC). Common elements in guidelines for prescribing opioids for chronic pain. https://www.cdc.gov/drugoverdose/pdf/common_elements_in_guidelines_for_prescribing_opioids-a.pdf. Published 2015. Accessed September 13, 2018.
  6. Debono M, Chan S, Rolfe C, Jones TH. Tramadol-induced adrenal insufficiency. Eur J Clin Pharmacol. 2011;67(8):865-867. [PubMed 21243342]
  7. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016 [published correction appears in MMWR Recomm Rep. 2016;65(11):295]. MMWR Recomm Rep. 2016;65(1):1-49. doi: 10.15585/mmwr.rr6501e1. [PubMed 26987082]
  8. Lӧwenstein O, Leyendecker P, Lux EA, et al, “Efficacy and Safety of Combined Prolonged-Release Oxycodone and Naloxone in the Management of Moderate/Severe Chronic Non-Malignant Pain: Results of a Prospectively Designed Pooled Analysis of Two Randomized, Double-Blind Clinical Trials,” BMC Clin Pharmacol, 2010, 10:12. [PubMed 20920236]
  9. Meyers RS, Thackray J, Matson KL, et al. Key Potentially Inappropriate Drugs in Pediatrics: The KIDs List. J Pediatr Pharmacol Ther. 2020;25(3):175-191. [PubMed 32265601]
  10. Oxycontin (oxycodone extended-release) (prescribing information). Stamford, CT: Purdue Pharma L.P.; December 2016.
  11. Sevarino K. Medically supervised opioid withdrawal during treatment for addiction. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 13, 2018.
  12. Smith K, Hopp M, Mundin G, et al, “Single- and Multiple-Dose Pharmacokinetic Evaluation of Oxycodone and Naloxone in an Opioid Agonist/Antagonist Prolonged-Release Combination in Healthy Adult Volunteers,” Clin Ther, 2008, 30(11):2051-68. [PubMed 19108793]
  13. Targin (oxycodone and naloxone) [product monograph]. Pickering, Ontario, Canada: Purdue Pharma; September 2020.
  14. Vondrackova D, Leyendecker P, Meissner W, et al, “Analgesic Efficacy and Safety of Oxycodone in Combination With Naloxone as Prolonged Release Tablets in Patients With Moderate to Severe Chronic Pain,” J Pain, 2008, 9(12):1144-54. [PubMed 18708300]
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