Oxycodone and Naloxone (Targin) combination pill is used for treating severe pain that requires an opioid analgesic. The combined use of naloxone alleviates the gastrointestinal problems associated with oxycodone.

Oxycodone and naloxone Uses:

Note: Not approved in the US.

• Pain management:

  • Pain control for which no other treatment is adequate and daily, round-the-clock, long-term opioid treatment is necessary

Note: Naloxone included in the formulation for the relief of opioid-induced constipation.

Oxycodone and Naloxone (Targin) Dose in Adults

Oxycodone and Naloxone (Targin) Dose in the treatment of pain management: Oral:

Note:

• Oxycodone 5 mg/naloxone 2.5 mg tablets are only to be used in titration or dose adjustment.
• It is not recommended to combine multiple oxycodone 5 mg/naloxone 2.5 mg pills with various tablet strengths.
• The maximum oxycodone dosage is 40 mg/20 mg of naloxone, or an overall daily dose of 80 mg/40 mg of naloxone.
• Only patients who are tolerant to opioids should take oxycodone 40 mg/naloxone 20 mg tablets. Patients who have been receiving opioid medication for at least a week at dosages greater than 60 mg of oral morphine or an equivalent are considered opioid tolerant.
• Opioid-naive patients:
  • starting dose:
    • Oxycodone 10 mg/naloxone 5 mg every 12 hours
• Opioid-experienced patients:
  • starting dose:
    • Currently on other oral oxycodone formulations:
    • Note: stop all other around-the oxycodone medications before beginning oxycodone/naloxone.
    • Start oxycodone/naloxone at the same total daily oral oxycodone dosage, in 2 equally divided doses every 12 hours.
  • Maximum single dose: Oxycodone 40 mg/naloxone 20 mg;
  • Maximum daily dose: Oxycodone 80 mg/naloxone 40 mg/day.
• Currently on other oral opioids:
  • stop all other around-the-clock opioids.
  • Start with oxycodone/naloxone as a bare minimum; rescue medication of sufficient strength should be provided.
  • Maximum single dose: Oxycodone 40 mg/naloxone 20 mg;
  • Maximum daily dose: Oxycodone 80 mg/naloxone 40 mg/day.

• Dose adjustment:

  • The dose is customized; titrate dose slowly every 1 to 2 days until adequate response and acceptable adverse effects.
  • The need for a dose adjustment rather than adjusting may be indicated by repeated pain at the end of the dosing interval.
  • Maximum single dose: Oxycodone 40 mg/naloxone 20 mg;
  • Maximum daily dose: Oxycodone 80 mg/naloxone 40 mg/day.
  • Patients that need rescue medication:
    • Patients who experience breakthrough pain may need rescue medication with an adequate dose of an immediate-release analgesic.
    • Note: Rescue medications used in clinical trials were immediate-release oxycodone or combination products containing codeine.
  • Administer a single dose of an immediate-release opioid that is around 16% of the equivalent daily dose of oxycodone.
  • Patients needing >2 doses daily of rescue medication should have oxycodone/naloxone dose titrated upward every 1 to 2 days until an adequate response is attained (no more than recommended maximum dosing).
  • The Dosing interval (every 12 hours) should not be adjusted.

• Discontinuation of therapy:

  • When discontinuing chronic opioid therapy, the dose should be slowly tapered down. An optimal universal tapering schedule for all patients has not been established.
  • Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days).
  • Tapering schedules should be individualized for minimum opioid withdrawal. An even slower taper may be used in patients who have been receiving opioids for a long duration (eg, years), especially in the final stage of tapering.
  • More rapid tapers may be used in patients having severe side effects.
  • Monitor carefully for signs/symptoms of withdrawal. If the patient shows withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing the amount of daily dose reduction, pausing the taper and resuming when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to decrease withdrawal symptoms.
  • Continue nonopioid analgesics as required for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasms) as required.

Use in Children:

Not indicated.

Oxycodone and Naloxone (Targin) Pregnancy Risk Category: C

• Contraindicated during pregnancy and labor.
• [Canadian Boxed Warn]: Babies exposed to oxycodone during pregnancy are at high risk for life-threatening respiratory depression. 
• A neonatal withdrawal syndrome can occur in newborns who have been exposed to opioids for a prolonged period of time. This could be potentially life-threatening.
• Long-term opioid abuse can cause secondary hypogonadism. This could lead to infertility or sexual dysfunction in both men as well as women.

Use of naloxone andoxycodone while breastfeeding

• Breastfeeding women are not advised to use contraindicated products.
• Breast milk contains oxycodone; however, it is unknown if breast milk contains naloxone.
• [Canadian Boxed Warn]: Babies exposed to oxycodone via breast milk may develop life-threatening respiratory depression

Oxycodone and Naloxone (Targin) Dose in Kidney Disease:

• Mild or moderate impairment:

  • Decrease dose to 33% to 50% of the usual starting dose; titrate cautiously; consider the use of alternative treatments without naloxone in patients with severe renal dysfunction.

• Severe impairment:

  • Contraindicated.

Oxycodone and Naloxone (Targin) Dose in Liver Disease:

• Mild impairment:

  • Initial: Reduce dose to 33% to 50% of the regular starting dose; titrate cautiously.

• Moderate to severe impairment:

  • Contraindicated.

Common Side Effects of Oxycodone and Naloxone (Targin):

• Hematologic & oncologic:

  • Cancer pain

Less Common Side Effects of Oxycodone and Naloxone (Targin):

• Central Nervous System:

  • Abdominal Pain
  • Withdrawal Syndrome
  • Weakness
  • Fatigue
  • Headache
  • Pain
  • Depression
  • Peripheral Pain
  • Sciatica
  • Drowsiness
  • Migraine
  • Tremor

• Dermatologic:

  • Hyperhidrosis
  • Skin Rash

• Endocrine & Metabolic:

  • Peripheral Edema
  • Increased Serum Glucose
  • Hyperglycemia
  • Hyperlipidemia
  • Hyperuricemia

• Gastrointestinal:

  • Anorexia
  • Nausea
  • Constipation
  • Vomiting
  • Xerostomia
  • Gastroenteritis

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Progression Of Cancer
  • Anemia
  • Decreased Hemoglobin

• Infection:

  • Viral Infection
  • Influenza

• Neuromuscular & Skeletal:

  • Back Pain
  • Lower Extremity Pain
  • Upper Extremity Pain
  • Osteoarthritis

• Respiratory:

  • Bronchitis
  • Sinusitis

Contraindications to Oxycodone and Naloxone (Targin):

• Hypersensitivity to oxycodone or naloxone (eg, anaphylaxis), or any component of the formula,
• Hypersensitivity to other opioids
• Moderate to severe hepatic impairment (Child Puugh classes B or C);
• severe renal impairment
• Known or suspected GI obstruction, or any disease that affects bowel movement;
• Suspected surgical abdomen (eg acute appendicitis, pancreatitis)
• You can manage mild, intermittent or short-term pain with other pain medication;
• Management of acute pain including outpatient and day surgery;
• Management of perioperative pain
• Acute or severe bronchial asthma, chronic obstruction of the airway or status as asthmaticus;
• Acute respiratory depression
• Cor pulmonale
• hypercapnia
• Convulsive disorders, acute alcoholism, and delirium tremens;
• Grave CNS depression can lead to increased cerebrospinal and intracranial pressure and head injuries.
• Concurrent use, or use within two weeks of MAOIs
• Patients who are opioid dependent and those who need withdrawal treatment for opioid dependence;
• Use in women who are pregnant, nursing, or during labor and birth
• rectal administration

There is not much evidence of cross-reactivity between opioids and allergenic substances. Cross-sensitivity is possible, but it cannot be completely ruled out.

Warnings and precautions

• CNS depression:

  • CNS depression can lead to mental or physical impairments. Patients should be cautious about driving or operating machinery that requires mental alertness.
  • Avoid using ethanol during therapy as it can increase CNS depression.

• Diarrhea:

  • Diarrhea can be caused by Naloxone; patients should report persistent or severe diarrhea for at least 3 days.

• Hyperalgesia:

  • This may occur with low doses of oxycodone. Dose reduction or an alternative opioid may be necessary.

• Hypotension

  • This medication can cause severe hypotension, including orthostatic hypotension, syncope, and heart disease.
  • Patients with hypovolemia, cardiac disease (including acute MI) or drugs that may increase hypotensive effects (e.g. phenothiazines and general anesthetics) should be cautious.
  • After starting or adjusting the dose, be aware of hypotension symptoms.
  • Patients with circulatory shock should not take oxycodone; the vasodilatory effects may worsen hypotension and lower cardiac output.

• Respiratory depression: [Canadian boxed warning]

  • Oxycodone/naloxone-ER may cause severe, life-threatening or fatal respiratory depression.
  • Monitor your respiratory health closely, especially if you are starting therapy or increasing the dose.
  • It is important to swallow the tablets whole.
  • Any efforts to chew, crush, break, or dissolve them could cause the instant release and ingestion of lethal doses of oxycodone.
  • Effects of respiratory depressants can emerge immediately if pain disappears all of a sudden.
  • Carefully adjusting the dose is necessary to lower the chance of developing respiratory depression.
  • Patients who have a tolerance to opioids of similar potency should be restricted from taking 40 mg/20 mg tablets. If they are unable to tolerate opioids, then fatal respiratory depression may occur.
  • The sedative effects of opioids can be exacerbated by carbon dioxide retention due to opioid-induced respiratory depression.

• Serotonin syndrome:

  • Seldom but potentially fatal serotonin syndromes have been reported with serotonergic drugs (eg, SSRIs and SNRIs), particularly when combined with other serotonergic medications.
  • Use with MAOIs and serotonin precursors only (eg l-tryptophan or oxitriptan). Do not combine with serotonergic agents such as triptans, TCAs. Stop treatment immediately if signs/symptoms develop.

• Adrenocortical Insufficiency

  • Opioid use can cause a condition called a "reproductive insufficiency"; this is usually experienced when opioid use exceeds one month.
  • Patients with Addison disease, adrenocortical impairment or other conditions should be cautious.
  • Dose adjustment may be necessary. Opioid use for long periods can lead to secondary hypogonadism. This could cause mood disorders or osteoporosis.

• Insufficiency of the biliary tract:

  • Patients with biliary dysfunction should be cautious; adjustment of dose may be necessary.
  • The sphincter Oddi may be constricted by Opioids

• Cardiovascular disease

  • Patients with a history of cardiovascular disease should be cautious.

• CNS depression:

  • Patients with severe CNS depression are advised to avoid this medication.

• Delirium tremens:

  • Patients with delirium-tremens are not advised to take this medication.

• Head trauma

  • Individuals who have experienced a head injury or have high ICP are contraindicated.

• Hepatic impairment

  • Patients with mild hepatic dysfunction should be cautious; dosing adjustments may be necessary.
  • Contraindicated in patients with severe to moderate hepatic dysfunction.

• Mental health conditions

  • Patients with mental health conditions such as depression, anxiety disorders, and post-traumatic stress disorder (PTS) should be cautious when using opioids for chronic pain.
  • There is a greater risk of opioid overdose and opioid use disorder. It is recommended to have more frequent monitoring.

• Obesity:

  • Patients who are obese or morbidly overweight should be treated with caution.

• Peritoneal carcinomatosis:

  • It is not recommended for patients with cancer-associated peritoneal carcinomatosis.

• Prostatic hyperplasia/urinary restriction:

  • Patients with prostatic hyperplasia or urinary stricture should be cautious. Dosage adjustment may be necessary.

• Psychosis:

  • Patients with toxic psychosis should be cautious; a dose adjustment may need to be made.

• Renal impairment

  • Patients with severe renal impairment should be cautious. Dose adjustment may be necessary. In severe renal impairment, use is not recommended.

• Respiratory disease

  • Patients with severe or acute bronchial asthma, chronic or persistent obstructive lung disease, cor Pulmonale, hypercapnia or acute respiratory depression are not recommended to use this medication.

• Seizures:

  • Patients with convulsive disorders should not take this medication.

• Sleep-disordered breathing

  • Patients with sleep-disordered sleeping disorders, such as HF or obesity, should be advised to avoid opioids for chronic pain. 
  • Patients with severe or moderate sleep-disordered sleeping should avoid opioids.

• Thyroid dysfunction:

  • Patients with thyroid dysfunction (eg hypothyroidism or myxedema) should be cautious. Dosage adjustment may be necessary.

Oxycodone and naloxone: Drug Interaction

Monitoring Parameters:

• Relief of pain, mental and respiratory problems, blood pressure
• Bowel function
• Signs and symptoms of abuse, misuse, or addiction
• Signs and symptoms of hypogonadism/hypoadrenalism

Chronic pain is long-term treatment that does not include end-of life or palliative care. It can also be active cancer treatment, sickle cells disease or medication-assisted opioid abuse disorder treatment.

• Within 1 to 4 weeks after treatment initiation, and as doses increase, you can assess the benefits and risks of opioid therapy.
• Patients at higher risk for overdose or those with opioid addiction should be re-evaluated every three months.
• Before starting, it is recommended that urine drug testing be done. Re-checking should occur at least once a year (includes prescription controlled medications and illicit drugs).

How to administer Oxycodone and Naloxone (Targin)?

Oral:

• Both with and without food, administer. One pill at a time, swallow whole; do not crush, cut, chew, dissolve, or divide.
• The uncontrolled release of oxycodone that results from breaking, chewing, crushing, cutting, dissolving, or splitting ER pills can cause overdose or death.
• Tablet administration via the rectal route is not advised due to an elevated risk of adverse effects from greater rectal absorption.

Mechanism of action of Oxycodone and Naloxone (Targin):

Oxycodone:

• Binds to the CNS opiate receptors, which causes inhibition of ascending pain pathways.
• This alters the perception and response to pain. Also produces generalized CNS depression.

Naloxone:

• It is a pure opioid antagonist, which competes with opioids at opioid receptor site, including the gut opioid receptors. This counteracts opioid-induced constipation.

Notification

• A controlled release formulation of oxycodone/naloxone has shown improved bowel function as well as similar pain relief efficacy to the controlled-release drug.

Notice:

• The pharmacokinetic characteristics of the controlled-release formulation of oxycodone and naloxone were similar to those of the drugs' individual administrations.

Naloxone:

• Bioavailability:
  • Oral: <3%
• Metabolism:
  • Primarily hepatic via glucuronidation
• Excretion:
  • Urine (as metabolites)

Oxycodone (controlled release):

• Duration:
  • ≤12 hours
• Distribution:
  • distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain.
• Protein binding:
  • ~45%
• Metabolism:
  • In the gut and liver to noroxycodone (via CYP3A4), oxymorphone (via CYP2D6), and noroxymorphone (via CYP2D6, CYP3A4); metabolites undergo glucuronidation.
  • Analgesic activity of metabolites may be of little clinical significance.
• Bioavailability:
  • Up to 87% (Note: Proportional bioavailability of oxycodone 5 mg/naloxone 2.5 mg tablets to other tablet strengths has not been established.)
• Half-life elimination:
  • 4.5 hours.
• Time to peak, plasma:
  • ~4 to 5 hours.
• Excretion:
  • Urine and feces (as parent drug and metabolites)

International Brand Names of Oxycodone and Naloxone:

• Targin
• Targin PR
• Targinact
• Targiniq

Oxycodone and Naloxone Brand Names in Pakistan:

No Brands Available in Pakistan.