oxycodone/naltrexone (Discontinued)

>10%

Nausea (14.4-20.5%)

Constipation (3.4-14.9%)

1-10%

Vomiting (6.2-9%)

Somnolence (0.7-9%)

Headache (1.4-7.3%)

Pruritus (2.1-6.6%)

Dizziness (4.1-5.9%)

Diarrhea (2.2-5.5%)

Dry mouth (3.2%)

Fatigue (3.2-3.4%)

Abdominal pain (1.4-2.9%)

Hyperhidrosis (2.4-2.7%)

Drug withdrawal symptoms (1-2.7%)

Muscle spasms (0.2-2.7%)

Hot flush (1.4-2.4%)

Back pain (1.2-2.1%)

Edema, peripheral (0.7-2.1%)

Arthralgia (0.7-2.1%)

Hypoesthesia (0-2.1%)

Oropharyngeal pain (0-2.1%)

Insomnia (0.7-2%)

Postmarketing Reports

Serotonin syndrome

Adrenal insufficiency; mostly with use exceeding 1 month

Anaphylaxis and pharyngeal edema

Androgen deficiency with long-term use

Myocardial ischemia and ventricular fibrillation reported with overdose

Contraindications

Patients with significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected GI obstruction, including paralytic ileus

Hypersensitivity (eg, anaphylaxis) to oxycodone or naltrexone or any other components of the formulation

Cautions

Contains oxycodone, a Schedule II controlled drug; as an opioid, oxycodone/naltrexone exposes users to the risks of addiction, abuse, and misuse; as extended-release products (eg, Troxyca ER) deliver the opioid over an extended period, there is a greater risk for overdose and death owing to the larger amount of oxycodone present (see Black Box Warnings)

Prolonged use during pregnancy can result in neonatal withdrawal syndrome that may be fatal if not recognized and managed by neonatal experts (see Black Box Warnings)

Adrenal insufficiency reported with opioid use (greater incidence if used >1 month); if adrenal insufficiency diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid

Severe hypotension reported, including orthostatic hypotension and syncope in ambulatory patients; risk increases in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazine, general anesthetics); monitor for severe hypotension during dosage initiation and titration; avoid use with circulatory shock

Oxycodone/naltrexone may further reduce respiratory drive and exacerbate CO2 retention in patients with increased ICP or brain tumors; may also obscure the clinical course in a patient with a head injury; avoid use with impaired consciousness or coma

Contraindicated with GI obstruction (see Contraindications); oxycodone may cause spasm of the sphincter of Oddi and increase serum amylase; monitor with biliary tract disease, including acute pancreatitis, for worsening symptoms

May increase risk of seizures; monitor with history of seizure disorders for worsened seizure control during therapy

Altering the drug by crushing, chewing, or dissolving the pellets within the capsule can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals

Gradually discontinue; do not stop drug abruptly (see Administration)

May impair mental or physical abilities needed to drive or operate machinery

Naltrexone does not interfere with thin-layer, gas-liquid, or high-pressure liquid chromatography for detection of morphine, methadone, oxycodone, or quinine in urine; naltrexone may or may not interfere with enzymatic methods for detecting opioids, depending on the sensitivity and specificity of the test

Respiratory depression

• Serious, life-threatening, or fatal respiratory depression has been reported with opioids, even when used as recommended; risk is greatest when initiating treatment or after increasing the dose
• Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered drug clearance compared with younger, healthier patients
• Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a 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
• Monitor these patients closely, particularly when initiating and titrating oxycodone/naltrexone, or if coadministered with other drugs that depress respiration; alternatively, consider using nonopioid analgesics
• Also see Black Box Warnings

Drug interaction overview

• CYP3A4 inhibitors and inducers

  • Oxycodone is a CYP3A4 and CYP2D6 substrate
  • Coadministration with CYP3A4 inhibitors (eg, macrolide antibiotics, azole antifungal agents, protease inhibitors) may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when a CYP3A4 inhibitor is added after a stable dose of oxycodone/naltrexone is achieved
  • Similarly, discontinuation of a CYP3A4 inducer (eg, rifampin, carbamazepine, phenytoin) in oxycodone/naltrexone-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions
  • When coadministering CYP3A4 inhibitors or discontinuing CYP3A4 inducers, monitor patients closely at frequent intervals and consider oxycodone/naltrexone dosage reduction until stable drug effects are achieved
  • These effects may be more pronounced with drugs that inhibit both CYP3A4 and CYP2D6
  • Coadministration with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone
  • When coadministering CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur
  • Also see Black Box Warnings

• CNS depressants

  • Hypotension, profound sedation, respiratory depression, coma, and death may result if coadministered with alcohol or other CNS depressants (eg, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids)
  • Assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression
  • Also evaluate alcohol use or illicit drug use
  • If the decision to begin oxycodone/naltrexone is made, start with a lower dosage, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dose of the concomitant CNS depressant

• Serotonergic drugs

  • Coadministration of opioids with other drugs (eg, SSRIs, SNRIs, TCAs, triptans, 5-HT3 antagonists, mirtazapine, trazodone, tramadol, MAOIs, linezolid, methylene blue) that affect the serotonergic neurotransmitter system may result in serotonin syndrome
  • If coadministration is warranted, carefully monitor, especially during treatment initiation or dose adjustment
  • Discontinue drug if serotonin syndrome suspected or evident

• Mixed agonist/antagonists and partial agonist opioid analgesics

  • Coadministration may precipitate withdrawal
  • Avoid use with mixed agonist/antagonist (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics

• Muscle relaxants

  • Opioids may enhance neuromuscular blockade and increase respiratory depression
  • Monitor for respiratory depression that may be more than expected with muscle relaxants; decrease dose of opioid, muscle relaxant, or both

• Monoamine oxidase inhibitors (MAOIs)

  • Coadministration with MAOIs can potentiate oxycodone effects and increase risk of anxiety, confusion, hypotension, respiratory depression, profound sedation, coma, and death
  • Avoid concomitant use with MAOIs or within 14 days of stopping an MAOI

• Diuretics

  • Opioids can decrease diuretic efficacy by inducing antidiuretic hormone release
  • Monitor for decreased diuresis and/or effects on blood pressure Increase diuretic dose as needed

• Anticholinergic drugs

  • Coadministration may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus
  • Monitor for signs of urinary retention or reduced GI motility

Pregnancy

Prolonged use during pregnancy may cause neonatal opioid withdrawal syndrome (see Black Box Warnings)

Lactation

Oxycodone is present in breast milk; because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, breastfeeding is not recommended during treatment with oxycodone/naltrexone

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.

Mechanism of Action

Opioid agonist/opioid antagonist combination product

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

Naltrexone: Opioid competitive receptor antagonist; shows highest affinity for mu receptors

Absorption

Bioavailability: 60-87% (oxycodone)

Peak plasma time: 12 hr (oxycodone)

Peak plasma concentration: Reduced by ~67% compared with immediate-release IR oxycodone

AUC: Equivalent to immediate-release oxycodone

Steady-state: Reached in 48 hr

Crushed capsule

• Analgesic activity primarily due to the parent drug oxycodone; oxycodone/naltrexone is designed to provide delivery of oxycodone over 12 hr
• Chewing, crushing, or dissolving the pellets within the capsules impairs the extended-release delivery mechanism and results in the rapid release and absorption of a potentially FATAL dose of oxycodone and a potentially complete release of sequestered naltrexone
• Peak plasma time (crushed capsule): 0.6-1 hr PO; 1.6 hr intranasal

Distribution

Vd: 2.6 L/kg

Protein bound: ~45%

Metabolism

Oxycodone is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides

CYP3A-mediated N-demethylation to an in active metabolite from noroxycodone is the principal metabolic pathway of oxycodone in humans

CYP2D6-mediated O-demethylation to an active metabolite oxymorphone is a minor metabolic pathway

Elimination

Half-life: ~7.2 hr (oxycodone)

Total plasma clearance: 0.8 L/min

Urinary excretion: 19% (free oxycodone); 50% (conjugated oxycodone); ~14% (conjugated oxymorphone)

Oral Administration

Swallow capsule whole

Instruct patients not to crush, chew, or dissolve the pellets in the capsule to avoid the risk of release and absorption of a potentially fatal dose of oxycodone and to avoid release of sequestered naltrexone that could precipitate opioid withdrawal

Alternatively, the capsule contents (ie, pellets) may be sprinkled on a small amount of applesauce (other foods have not been tested) and swallowed immediately without chewing; rinse mouth with water and swallow to ensure all pellets have been swallowed

Do not administer pellets through NG or G-tube

Discontinuation

• Do not abruptly discontinue
• Taper the dose gradually, by 25-50% q2-4 days, while monitoring carefully for signs and symptoms of withdrawal
• If withdrawal signs or symptoms occur, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both

Opioid Tolerant Patients

60 mg/7.2 mg and 80 mg/9.6 mg capsules, single doses >40 mg/4.8 mg, or a total daily dose >80 mg/9.6 mg are only for patients in whom tolerance to an opioid of comparable potency has been established

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals

Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse

Conversion from other PO oxycodone

• Patients receiving other oral oxycodone formulations may be converted to oxycodone/naltrexone by administering 50% of the patient’s total daily PO oxycodone dose as Troxyca ER q12hr

Conversion from other opioids

• Discontinue all other around-the-clock opioid drugs when initiating oxycodone/naltrexone
• When converting patients to oxycodone/naltrexone, 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

• Conversion factors to oxycodone

  • Codeine: 0.1
  • Hydrocodone: 0.67
  • Hydromorphone: 2.67
  • Morphine: 0.67
  • Oxycodone: 1

• Calculate ~total daily PO oxycodone dose

  • Multiply current total daily dose of the opioid by the conversion factor listed above by appropriate conversion factor (if >1 opioid, calculate total daily for each opioid factor and add the sum totals)
  • Use only the opioid component to calculate total daily dose of combination opioid/nonopioid analgesics
  • Reduce the estimated total daily oxycodone dose by 50% to obtain the daily dose of Troxyca ER; divide this daily dose in half to obtain the q12hr dose
  • After conversion, if the total daily opioid requirement is ≤20 mg/day of oxycodone, initiate with Troxyca ER 10 mg/1.2 mg q12hr
  • Always round the dose down, if necessary, to the appropriate Troxyca ER strength
  • Provide prompt-acting rescue analgesic as needed (eg, immediate-release oxycodone)
  • Reevaluate total daily dose (scheduled plus short-acting rescue medication) to adjust dose; additionally, monitor for any signs of opioid withdrawal

• Conversion example

  • Hydrocodone extended-release 30 mg PO q12hr = 60 mg/day
  • 60 mg hydrocodone x 0.67 (conversion factor) = oxycodone 40.2 mg/day
  • Oxycodone 40.2 mg/day reduced by 50% ~20 mg/day
  • Divided 20 mg/day in half to obtain the q12hr Troxyca ER dose; for this example, it would be 10 mg/1.2 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

Conversion from transdermal fentanyl

• May initiate oxycodone/naltrexone 18 hr after removing transdermal fentanyl patch
• A conservative estimated dose of 10 mg/1.2 mg PO q12hr oxycodone/naltrexone should be substituted for each 25-mcg/hr fentanyl patch
• Monitor closely during conversion; limited documented experience with this conversion

Conversion from transdermal buprenorphine

• There has been no systematic assessment of this conversion
• Initiate oxycodone/naltrexone 10 mg/1.2 mg PO q12hr
• Monitor closely during conversion; limited documented experience with this conversion

Conversion from tramadol

• Tramadol has both serotonergic and opioid activity, and there has been no systematic assessment of this conversion
• Initiate oxycodone/naltrexone 10 mg/1.2 mg PO q12hr
• Monitor closely during conversion; limited documented experience with this conversion

Storage

Store at 25°C (77°F); excursions permitted from 15-30°C (59-86°F)

Dispense in tight (USP), light-resistant, child-resistant containers

Instruct patients to take steps to store securely and dispose of unused drug by flushing the capsules down the toilet