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Oxycodone and Acetaminophen

Pronunciation

Pronunciation

(oks i KOE done & a seet a MIN oh fen)

Index Terms

  • Acetaminophen and Oxycodone
  • Oxycodone HCl/Acetaminophen
  • Oxycodone/Acetominophen
  • Tylox

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral: 5/500: Oxycodone hydrochloride 5 mg and acetaminophen 500 mg [DSC]

Solution, Oral:

Roxicet: Oxycodone hydrochloride 5 mg and acetaminophen 325 mg per 5 mL (5 mL, 500 mL) [contains ethanol <0.5%; mint flavor]

Tablet, Oral: 2.5/325: Oxycodone hydrochloride 2.5 mg and acetaminophen 325 mg; 5/325: Oxycodone hydrochloride 5 mg and acetaminophen 325 mg; 7.5/325: Oxycodone hydrochloride 7.5 mg and acetaminophen 325 mg; 7.5/500: Oxycodone hydrochloride 7.5 mg and acetaminophen 500 mg [DSC]; 10/325: Oxycodone hydrochloride 10 mg and acetaminophen 325 mg; 10/650: Oxycodone hydrochloride 10 mg and acetaminophen 650 mg [DSC]

Endocet 2.5/325: Oxycodone hydrochloride 2.5 mg and acetaminophen 325 mg

Endocet 5/325 [scored]: Oxycodone hydrochloride 5 mg and acetaminophen 325 mg

Endocet 7.5/325: Oxycodone hydrochloride 7.5 mg and acetaminophen 325 mg

Endocet 7.5/500: Oxycodone hydrochloride 7.5 mg and acetaminophen 500 mg [DSC]

Endocet 10/325: Oxycodone hydrochloride 10 mg and acetaminophen 325 mg

Endocet 10/650: Oxycodone hydrochloride 10 mg and acetaminophen 650 mg [DSC]

Magnacet 5/400: Oxycodone hydrochloride 5 mg and acetaminophen 400 mg [DSC]

Magnacet 7.5/400: Oxycodone hydrochloride 7.5 mg and acetaminophen 400 mg [DSC]

Magnacet 10/400: Oxycodone hydrochloride 10 mg and acetaminophen 400 mg [DSC]

Percocet 2.5/325: Oxycodone hydrochloride 2.5 mg and acetaminophen 325 mg

Percocet 5/325 [scored]: Oxycodone hydrochloride 5 mg and acetaminophen 325 mg

Percocet 7.5/325: Oxycodone hydrochloride 7.5 mg and acetaminophen 325 mg

Percocet 7.5/500: Oxycodone hydrochloride 7.5 mg and acetaminophen 500 mg [DSC]

Percocet 10/325: Oxycodone hydrochloride 10 mg and acetaminophen 325 mg

Percocet 10/650: Oxycodone hydrochloride 10 mg and acetaminophen 650 mg [DSC]

Primlev 5/300: Oxycodone hydrochloride 5 mg and acetaminophen 300 mg

Primlev 7.5/300: Oxycodone hydrochloride 7.5 mg and acetaminophen 300 mg

Primlev 10/300: Oxycodone hydrochloride 10 mg and acetaminophen 300 mg

Roxicet 5/325 [scored]: Oxycodone hydrochloride 5 mg and acetaminophen 325 mg

Tablet, Extended Release, Oral:

Xartemis XR: Oxycodone hydrochloride 7.5 mg and acetaminophen 325 mg

Brand Names: U.S.

  • Endocet
  • Percocet
  • Primlev
  • Roxicet
  • Xartemis XR
  • Xolox [DSC]

Pharmacologic Category

  • Analgesic Combination (Opioid)
  • Analgesic, Opioid

Pharmacology

Oxycodone, as with other opioid analgesics, blocks pain perception in the cerebral cortex by binding to specific receptor molecules (opiate receptors) within the neuronal membranes of synapses. This binding results in a decreased synaptic chemical transmission throughout the CNS thus inhibiting the flow of pain sensations into the higher centers. Mu and kappa are the two subtypes of the opiate receptor to which oxycodone binds to cause analgesia.

Acetaminophen inhibits the synthesis of prostaglandins in the CNS and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center.

Onset of Action

Onset of action: Within 10 to 15 minutes; Peak effect: Within 1 hour

Duration of Action

3 to 6 hours

Use: Labeled Indications

Acute pain (extended-release): Management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate.

Limitations of use: Because of the risks of addiction, abuse, misuse, overdose, and death with opioids, even at recommended doses, reserve extended-release (ER) for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate.

Moderate to moderately severe pain (immediate release): Management of moderate to moderately-severe pain

Contraindications

Hypersensitivity to oxycodone, acetaminophen, or any component of the formulation; severe respiratory depression (in absence of resuscitative equipment or ventilatory support); bronchial asthma (acute or severe) or hypercarbia; paralytic ileus (suspected or known)

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.

Dosing: Adult

Note: Initial dose is based on the oxycodone content; however, the maximum daily dose is based on the acetaminophen content.

Extended-release: Acute pain: Oral: Usual dose: 2 tablets every 12 hours; the second initial dose may be administered as early as 8 hours after the first initial dose if needed; subsequent doses are to be administered 2 tablets every 12 hours. Do not exceed acetaminophen 4 g daily. NOTE: Oxycodone/acetaminophen ER is not interchangeable with other oxycodone/acetaminophen products because of differing pharmacokinetic profiles that affect the frequency of administration.

Discontinuation: Do not stop abruptly in patients who may be physically dependent gradually decrease the dose by 50% every 2 to 4 days to prevent signs and symptoms of withdrawal.

Immediate release: Management of pain: Oral: Doses should be titrated to appropriate analgesic effects.

Manufacturer’s labeling: Moderate to moderately severe pain: Initial dose, based on oxycodone content: 2.5-10 mg every 6 hours as needed. Titrate according to pain severity and individual response. Do not exceed acetaminophen 4 g daily.

Alternate recommendations (APS, 2008):

Moderate pain (off-label): Initial dose, based on oxycodone content: 5 mg. Doses typically given every 4-6 hours as needed; manufacturer’s labeling recommends every 6 hours as needed. Do not exceed acetaminophen 4 g daily.

Severe pain (off-label): Initial dose, based on oxycodone content: 10-20 mg. Doses typically given every 4-6 hours as needed; manufacturer’s labeling recommends every 6 hours as needed. Do not exceed acetaminophen 4 g daily.

Dosing: Geriatric

Management of pain: Oral:

No dosage adjustment provided in manufacturer’s labeling; however, use with caution and consider decreasing the initial dose and/or increasing the frequency.

Severe pain (off-label dosing): Immediate release: Elderly >70 years: Consider decreasing the initial dose (based on oxycodone content) by 25% to 50%, then titrating the dose upward or downward as needed; monitor frequently during titration. Do not exceed acetaminophen 4 g daily (APS, 2008).

Dosing: Pediatric

Note: Initial dose is based on the oxycodone content; however, the maximum daily dose is based on the acetaminophen content.

Management of pain: Children and Adolescents (off-label; American Pain Society [APS], 2008): Oral: Immediate-release: Doses should be titrated to appropriate analgesic effects:

Moderate pain: Initial dose,based on oxycodone content: 0.1-0.2 mg/kg/dose. Doses typically given every 4-6 hours as needed; manufacturer’s labeling recommends every 6 hours as needed; maxi mum initial oxycodone dose: 5 mg/dose. Do not exceed maximum daily acetaminophen dose: Children <45 kg: 90 mg/kg/day; Children ≥45 kg: 4000 mg daily

Severe pain: Initial dose, based on oxycodone content: 0.2 mg/kg/dose. Doses typically given every 4-6 hours as needed; manufacturer’s labeling recommends every 6 hours as needed; maximum initial oxycodone dose: 10 mg. Do not exceed maximum daily acetaminophen dose: Children <45 kg: 90 mg/kg/day; Children ≥45 kg: 4000 mg daily

Dosing: Renal Impairment

Extended-release: Initial dose: One tablet every 12 hours; adjust dose as needed.

Immediate-release: There are no dosage adjustments provided in manufacturer’s labeling. Use with caution; reduced clearance in severe impairment may require dosage adjustment.

Dosing: Hepatic Impairment

Extended-release: Initial dose: One tablet every 12 hours; adjust dose as needed.

Immediate-release: There are no dosage adjustments provided in manufacturer’s labeling. Use with caution; reduced clearance in severe impairment may require dosage adjustment.

Administration

Administer without regards to food. Swallow ER 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.

Storage

Extended-release: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Immediate-release: Store at 20°C to 25°C (68°F to 77°F). Protect from moisture.

Drug Interactions

Alcohol (Ethyl): May enhance the hepatotoxic effect of Acetaminophen. Monitor therapy

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

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

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

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

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

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

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

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

Busulfan: Acetaminophen may increase the serum concentration of Busulfan. Monitor therapy

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

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Consider therapy modification

CNS Depressants: May enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

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

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

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

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

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

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

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

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

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Monitor therapy

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Monitor therapy

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

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

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

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

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

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

MetyraPONE: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Monitor therapy

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

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

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

Mipomersen: Acetaminophen may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

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

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

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

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

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

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

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

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

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

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

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

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

Phenylephrine (Systemic): Acetaminophen may increase the serum concentration of Phenylephrine (Systemic). Monitor therapy

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

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

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Consider therapy modification

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

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

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

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

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

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

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

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

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

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

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

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Consider therapy modification

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

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

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

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

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

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

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

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

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Monitor therapy

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

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

Test Interactions

See individual agents.

Adverse Reactions

Also see individual agents. Frequency not always defined.

>10%:

Central nervous system: Dizziness (13%)

Gastrointestinal: Nausea (31%)

1% to 10%:

Cardiovascular: Peripheral edema (1%), circulatory depression, hypotension, shock

Central nervous system: Headache (10%), drowsiness (4%), fatigue (≥1%), insomnia (≥1%), dysphoria

Dermatologic: Skin rash (2%) erythema (1%), excoriation (1%), pruritus (1%), skin blister (1%) , erythematous dermatitis

Endocrine & metabolic: Hot flash (1%)

Gastrointestinal: Vomiting (9%), constipation (4%), diarrhea (≥1%), dyspepsia (≥1%), xerostomia (≥1%)

Genitourinary: Dysuria (1%)

Hematologic & oncologic: Hemolytic anemia, neutropenia, pancytopenia, thrombocytopenia

Hepatic: Increased liver enzymes (≥1%)

Respiratory: Cough (≥1%), apnea, respiratory arrest, respiratory depression

<1% (Limited to important or life-threatening): Abdominal pain, acidosis, agitation, alkalosis, altered mental status, anxiety, arthralgia, aspiration, asthma, bradycardia, cardiac arrhythmia, cerebral edema, chest discomfort, chills, cognitive dysfunction, confusion, decreased appetite, dehydration, depression, dermatitis, diaphoresis, disorientation, dysphoria, drug abuse, drug dependence, drug overdose (accidental and nonaccidental), dysgeusia, dyspnea, ecchymoses, emotional lability, esophageal spasm, euphoria, eye redness, falling, fever, flushing, hallucination, hearing loss, hepatic failure, hepatitis, hepatotoxicity, hiccups, hyperglycemia, hyperhidrosis, hyperkalemia, hypersensitivity, hypersensitivity reaction, hypertension, hypoesthesia, hypoglycemia, hypothermia, hypoventilation, impaired consciousness, increased blood pressure, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, increased serum bilirubin, interstitial nephritis, intestinal obstruction, jitteriness, laryngeal edema, lethargy, malaise, memory impairment, metabolic acidosis, migraine, miosis, musculoskeletal chest pain , musculoskeletal stiffness, myalgia, myoclonus, noncardiac chest pain, obstructive sleep apnea hypopnea syndrome, oropharyngeal pain, orthostatic hypotension, palpitations, pancreatitis, paresthesia, proteinuria, pulmonary edema, renal failure, renal insufficiency, renal papillary necrosis, respiratory alkalosis, reduced urine flow, respiratory depression, rhabdomyolysis, sedation, seizure, sleep disorder, stupor, suicide, tachycardia, tachypnea, tinnitus, tremor, urinary retention, visual disturbance, weakness, withdrawal syndrome

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

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

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of oxycodone/acetaminophen ER. Monitor for respiratory depression, especially during initiation of oxycodone/acetaminophen or following a dose increase. Instruct patients to swallow oxycodone/acetaminophen ER whole; crushing, chewing, or dissolving oxycodone/acetaminophen can cause rapid release and absorption of a potentially fatal dose of oxycodone.

Accidental exposure:

Accidental ingestion of oxycodone/acetaminophen ER, especially in children, can result in a fatal overdose of oxycodone.

Neonatal opioid withdrawal syndrome:

Prolonged use of oxycodone/acetaminophen ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Hepatotoxicity:

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limit (4,000 mg/day), and often involve more than 1 acetaminophen-containing product.

Warnings/Precautions

Concerns related to adverse effects:

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

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

• Hepatotoxicity: [US Boxed Warning]: Acetaminophen may cause severe hepatotoxicity, potentially requiring liver transplant or resulting in death; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day in adults). Risk is increased with alcohol use, preexisting liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients.

• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur. Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Hypotension: May cause hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). May produce orthostatic hypotension in ambulatory patients. Use with caution to patients in circulatory shock.

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur with use of oxycodone/acetaminophen ER. Monitor for respiratory depression, especially during initiation of therapy or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration is essential. Overestimating the oxycodone/acetaminophen ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.

• Skin reactions: Serious and potentially fatal skin reactions, including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have occurred rarely with acetaminophen use. Discontinue therapy at the first appearance of skin rash.

Disease-related concerns:

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

• Abuse potential: [US Boxed Warning]: Oxycodone/acetaminophen ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing oxycodone/acetaminophen ER, and monitor all patients regularly for the development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk for misuse include younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]). Abuse or misuse of XR tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the oxycodone and can result in overdose and death

• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).

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

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

• G6PD deficiency: Use with caution in patients with known G6PD deficiency.

• GI disorders: Due to characteristics of the ER formulation that cause the tablets to swell and become sticky when wet, consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small GI lumen.

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

• Hepatic impairment: Use with caution in patients with hepatic impairment. Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.

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

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

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

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

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use oxycodone with caution in patients with pre-existing respiratory compromise (hypoxia and/or hypercapnia), cor pulmonale, COPD or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.

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

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

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

Concurrent drug therapy issues:

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

• Sedatives: Effects may be potentiated when used with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

Special populations:

• Debilitated patients: Use with caution in debilitated patients; there is a greater potential for respiratory depression.

• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects, such as respiratory depression. Oxycodone clearance may also be slightly reduced in the elderly. Dosage adjustments may be necessary. 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 (Dowell [CDC 2016]).

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of oxycodone/acetaminophen during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn of risk to the neonate. 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.

• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postop patients receiving opioids.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Extended-release tablets: Do not to presoak, lick or otherwise wet ER tablets prior to placing in the mouth; take one tablet at a time with enough water to ensure complete swallowing. Do not break, chew, crush, cut, dissolve or split the ER tablets; breaking, chewing, crushing, cutting, dissolving or splitting will result in uncontrolled delivery of oxycodone and can lead to overdose or death.

• Interchangeability: Oxycodone/acetaminophen ER is not interchangeable with other oxycodone/acetaminophen products because of differing pharmacokinetic profiles that affect the frequency of administration.

• Sulfites: Some preparations contain sulfites which may cause allergic reactions.

Other warnings/precautions:

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

• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day in adults. Do not use oxycodone/acetaminophen concomitantly with other acetaminophen-containing products.

• Overdose: [US Boxed Warning]: Accidental ingestion of oxycodone/acetaminophen ER, especially in children, can result in a fatal overdose of oxycodone.

• Withdrawal: Concurrent use of agonist/antagonist analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms. Do not abruptly stop ER tablets in patients who may be physically dependent; gradually decrease dose by 50% every 2 to 4 days to prevent signs and symptoms of withdrawal.

Monitoring Parameters

Monitor for pain relief, respiratory and mental status, blood pressure, constipation; signs or symptoms of hypogonadism or hypoadrenalism (Brennan, 2013)

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

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Refer to individual monographs for additional information.

[U.S. Boxed Warning]: Prolonged use of oxycodone/acetaminophen during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome.

Patient Education

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

• Patient may experience fatigue, vomiting, or nausea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe dizziness, passing out, difficulty breathing, slow breathing, shallow breathing, illogical thinking, severe constipation, loss of strength and energy, burning or numbness feeling, urinary retention, change in amount of urine passed, tachycardia, bradycardia, arrhythmia, chills, pharyngitis, hallucinations, mood changes, hearing loss, seizures, severe headache, severe abdominal pain, tremors, bruising, bleeding, vision changes, angina, memory impairment, abnormal gait, difficulty speaking, swelling of arms or legs, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

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

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

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