oxycodone/naloxone (Rx)

Brand and Other Names:Targiniq ER
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Dosing & Uses

AdultPediatricGeriatric

Dosing Forms & Strengths

oxycodone/naloxone

extended-release tablet: Schedule II

  • 10 mg/5 mg
  • 20 mg/10 mg
  • 40 mg/20 mg

Chronic Pain

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

Use as first opioid analgesic or in non-opioid tolerant patients

  • Starting dose: 10 mg/5 mg PO q12hr
  • Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

Titration and maintenance

  • May be up-titrated from current dose by increasing by 10 mg/5 mg q12hr q1-2 days as needed based on efficacy, safety, and tolerability
  • Not to exceed daily dose of 80 mg/40 mg (ie, 40 mg/20 mg q12hr)
  • If breakthrough pain experienced, assess need for a dosage increase or a rescue dose of an immediate-release analgesic

Opioid tolerant patients

  • Patients who are opioid tolerant are those receiving the following for ≥1 week:
  • -≥60 mg/day PO morphine
  • -≥25 mcg/hr transdermal fentanyl
  • -≥30 mg/day PO oxycodone
  • -≥8 mg/day PO hydromorphone
  • -≥25 mg/day PO oxymorphone, OR
  • -Equianalgesic dose of another opioid

Conversion to oxycodone/naloxone

Conversion from other PO oxycodone

  • Administer one-half of the patient's total daily PO oxycodone dose as Targiniq ER q12hr
  • Not to exceed daily dose of 80 mg/40 mg (ie, 40 mg/20 mg q12hr)

Conversion from other opioids

  • Discontinue all other around-the-clock opioid drugs when initiating oxycodone/naloxone
  • When converting patients to oxycodone/naloxone, it is safer to underestimate a patient’s 24-hr oral oxycodone requirements and provide rescue medication (eg, immediate-release opioid) than to overestimate the 24-hr oral oxycodone requirements, which could result in adverse reactions
  • First convert current opioid to equivalent daily PO morphine dose, and then convert the morphine equivalent daily dose to the recommended oxycodone/naloxone dose (see Prescribing information for conversion table and example)
  • Then convert from equivalent daily PO morphine dose to oxycodone/naloxone (see following):
  • -Morphine 20 mg to <70 mg PO: 10 mg/5 mg PO q12hr
  • -Morphine 70 mg to <110 mg PO: 20 mg/10 mg PO q12hr
  • -Morphine 110 mg to <150 mg PO: 30 mg/15 mg PO q12hr
  • -Morphine 150-160 mg PO: 40 mg/20 mg PO q12hr

Conversion from methadone

  • Close monitoring is essential when converting from methadone to other opioid agonists
  • The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure
  • Methadone has a long half-life and can accumulate in plasma

Conversion from transdermal fentanyl

  • May initiate oxycodone/naloxone 18 hr after removing transdermal fentanyl patch
  • A conservative estimated dose of ~10 mg/5 mg q12hr oxycodone/naloxone should be substituted for each 25 mcg/hr fentanyl patch
  • Not to exceed daily dose of 80 mg/40 mg (ie, 40 mg/20 mg q12hr)
  • Monitor closely during conversion; limited documented experience with this conversion

Conversion from transdermal buprenorphine

  • Transdermal buprenorphine <20 mcg/hr: oxycodone/naloxone 10 mg/5 mg q12hr oxycodone/naloxone
  • Not to exceed daily dose of 80 mg/40 mg (ie, 40 mg/20 mg q12hr)
  • Monitor closely during conversion; limited documented experience with this conversion

Dosage Modifications

Hepatic impairment

  • Mild: Reduce dose by one-third to one-half of the usual starting dose followed by careful titration
  • Moderate-to-severe: Contraindicated

Renal impairment

  • Reduce dose by one-half of the usual starting dose followed by careful dose titration

Dosing Considerations

Not indicated for prn analgesic

Administration

May take with or without food

Tablets must be swallowed intact and are not to be cut, broken, chewed, crushed, or dissolved (risk of rapid release and absorption of potentially fatal overdose)

Do not abruptly discontinue in a physically dependent patient; use a gradual downward titration to prevent withdrawal (see Prescribing information for suggested taper schedule)

<18 years: Safety and efficacy not established

See adult dosing

Higher oxycodone AUC (18% increase) and higher naloxone AUC (82% increase) for patients aged ≥65 yr compared with younger patients

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Interactions

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            Adverse Effects

            1-10%

            Nausea (7-8%)

            Vomiting (2-5%)

            Headache (3-4%)

            Constipation (3%)

            Abdominal pain (3%)

            Back pain (3%)

            Anxiety (1-3%)

            Pruritus (2%)

            Insomnia (1-2%)

            Postmarketing Reports

            Gastrointestinal disorders: Abdominal pain, constipation, diarrhea, nausea, and vomiting

            General disorders and administration site conditions: Drug withdrawal syndrome, fatigue, pain, malaise, and drug ineffective

            Injury, poisoning, and procedural complications: Inadequate analgesia

            Neoplasms benign, malignant, and unspecified (including cysts and polyps): Malignant neoplasm progression

            Nervous system disorders: Dizziness, headache, tremor, and somnolence

            Psychiatric disorders: Restlessness, confusional state, and anxiety

            Respiratory, thoracic, and mediastinal disorders: Dyspnea

            Skin and subcutaneous tissue disorders: Hyperhidrosis and pruritus

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            Warnings

            Black Box Warnings

            Exposes users to risks of addiction, abuse and misuse, which can lead to overdose and death; assess each patient’s risk before prescribing and monitor regularly for development of these behaviors and conditions

            Serious, life-threatening, or fatal respiratory depression may occur; monitor closely, especially upon initiation or following a dose increase

            Instruct patients to swallow extended-release tablets whole to avoid exposure to a potentially fatal dose of oxycodone

            Accidental ingestion, especially in children, can result in a fatal overdose of oxycodone

            Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated; 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

            Initiation of CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone

            Contraindications

            Significant respiratory depression

            Acute or severe bronchial asthma

            Known or suspected paralytic ileus and GI obstruction

            Known hypersensitivity to oxycodone or naloxone

            Moderate-to-severe hepatic impairment

            Cautions

            Cases of serotonin syndrome, a potentially life-threatening condition, reported with concomitant use of serotonergic drugs; this may occur within the recommended dosage range; the onset of symptoms generally occur within several hours to a few days of concomitant use, but may occur later than that; discontinue therapy immediately if serotonin syndrome is suspected

            While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24 to 72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of opioid

            Deaths have occurred in nursing infants exposed to high levels of opioid in breast milk because mothers were ultra-rapid metabolizers of opioid

            Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate

            Use in patients with acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment is contraindicated; patients with significant chronic obstructive pulmonary disease or cor pulmonale, and with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages

            Monoamine oxidase inhibitors (MAOIs) may potentiate effects of opioid, opioid’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of initiating or stopping MAOIs

            Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers; other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency

            Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

            Opioid pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension

            Oxycodone exposes users to the risks of addiction, abuse, and misuse; the tablet is designed to deliver oxycodone over an extended period and contains a larger amount of oxycodone

            Do not ingest alcohol or OTC medications containing alcohol while taking opioid analgesics

            Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death; if coadministration is required, consider dose reduction of 1 or both drugs

            Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression

            May cause severe hypotension, including orthostatic hypotension and syncope; this risk is increased in patients whose ability to maintain blood pressure has been compromised by reduced blood volume or coadministration with certain CNS depressants (eg, phenothiazines, general anesthetics)

            Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression; avoid use in patients with impaired consciousness or coma susceptible to intracranial effects of carbon dioxoide retention

            Symptoms consistent with opioid withdrawal occurred in some patients in the clinical trials; monitor patients for symptoms of withdrawal during treatment

            Concomitant use of CYP3A4 inhibitors may increase opioid effects

            CYP3A4 inducers may increase oxycodone clearance, leading to decreased oxycodone plasma concentrations, decreased efficacy, or abstinence syndrome in physically dependent patients

            May cause spasm of the sphincter of Oddi; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms (also see Contraindications)

            Opioids may cause increases in the serum amylase

            May aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings

            May impair the mental or physical abilities needed to perform potentially hazardous activities

            Avoid the use of mixed agonist/antagonist (ie, pentazocine, nalbuphine, butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic; mixed agonist/antagonists may reduce the analgesic effect and/or may precipitate withdrawal symptoms

            Do not abruptly discontinue; gradually taper the dose to avoid withdrawal symptoms

            Prolonged use during pregnancy can result in withdrawal symptoms in the newborn

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            Pregnancy & Lactation

            Pregnancy

            Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome; there are no available data in pregnant women to inform a drug associated risk for major birth defects and miscarriage; published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects

            Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of drug by newborn; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

            Severe fetal bradycardia reported when administered during labor; naloxone may reverse these effects; although there are no reports of fetal bradycardia earlier in pregnancy, it is possible it may occur; drug should be used in pregnancy only if clearly needed, if potential benefit outweighs risk to fetus, and if appropriate measures such as fetal monitoring are taken to detect and manage potential adverse effect on fetus

            Labor or delivery

            • Opioids cross placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in neonate; drug is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions that temporarily reduce strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

            Fertility

            • Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential; it is not known whether effects on fertility are reversible

            Lactation

            Drug is present in breast milk; published lactation studies report variable concentrations of drug in breast milk with administration of immediate-release formulation to nursing mothers in early postpartum period

            The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy; capsules and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

            Monitor infants exposed to drug through breast milk for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast- feeding is stopped

            Do not initiate oxycodone/naloxone in breastfeeding women because of the possibility of sedation or respiratory depression in an infant

            Withdrawal signs can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped or when breastfeeding is stopped; naloxone may precipitate opioid withdrawal in a breast-fed infant whose mother received opioid analgesics

            Pregnancy Categories

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

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

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

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

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

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

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

            Naloxone: Antagonist of mu, kappa, and delta opioid receptors, with greatest affinity for the mu receptor; produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally

            Absorption

            Bioavailability: 60-87% (oxycodone); 31% (naloxone)

            Single dose

            • Peak plasma time: 3-3.5 hr (oxycodone); 1.5-5 hr (naloxone)
            • Peak plasma concentration: 12.1-40.9 ng/mL (oxycodone); 0.306-0.845 ng/mL (naloxone)
            • AUC: 130-506 ng•hr/mL (oxycodone); 0.136-0.833 ng•hr/mL (naloxone)

            Multiple dose

            • Peak plasma time: 1.75-2 hr (oxycodone); 3.75-5 hr (naloxone)
            • Peak plasma concentration: 15-57 ng/mL (oxycodone); 0.0725-0.217 ng/mL (naloxone)
            • AUC: 129-507 ng•hr/mL (oxycodone); 0.416-1.55 ng•hr/mL (naloxone)

            Distribution

            Protein bound: <24% (oxycodone); <60% (naloxone)

            Vd: 245 L (oxycodone); 378 L (naloxone)

            Metabolism

            Oxycodone

            • Primarily metabolism by CYP3A4/5 and CYP2D6
            • Metabolites: Noroxycodone, oxymorphone, and noroxymorphone

            Naloxone

            • Primarily metabolized by UGT1A8 and UGT2B7
            • Metabolites: 6β-naloxol, naloxone-3β-glucuronide and 6 β-naloxol-3 β-glucuronide

            Elimination

            Half-life: 3.9-5.3 hr (oxycodone); 4.1-17.2 hr (naloxone)

            Total plasma clearance: 47.8 L/hr (oxycodone); 217 L/hr (naloxone)

            Renal clearance: 3.66-4.37 L/hr (oxycodone); 7.85-31.9 L/hr (naloxone)

            Excretion: 72% urine; also excreted in feces (oxycodone)

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.