Dosing and uses of Targiniq ER (oxycodone/naloxone)
Adult dosage forms and 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)
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Geriatric dosage forms and strengths
See adult dosing
Higher oxycodone AUC (18% increase) and higher naloxone AUC (82% increase) for patients aged ≥65 yr compared with younger patients
Targiniq ER (oxycodone/naloxone) adverse (side) 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
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
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
Pregnancy and lactation
Pregnancy category: C; caution if used for prolonged periods or near term
Prolonged use of opioid analgesics during pregnancy can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth
Lactation: Oxycodone is excreted into human breast milk; unknown if naloxone is distributed in human breast milk
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.
Pharmacology of Targiniq ER (oxycodone/naloxone)
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)
