Oxycodone

Profound sedation, respiratory depression, coma, and death may result if oxycodone is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., non-benzodiazepines 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.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.

Advise both patients and caregivers about the risks of respiratory depression and sedation when oxycodone is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone is used concomitantly with anticholinergic drugs.

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone if serotonin syndrome is suspected.

Examples: selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT₃ receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

The concomitant use of oxycodone and CYP3A4 inducers can decrease the plasma concentration of oxycodone, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use is necessary, consider increasing the oxycodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone dosage reduction and monitor for signs of respiratory depression.

Examples: rifampin, carbamazepine, phenytoin.

The concomitant use of oxycodone and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.

If concomitant use is necessary, consider dosage reduction of oxycodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

Examples: macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir).

Patients with mild to moderate renal impairment should be treated with caution. The lowest dose should be given with careful titration to pain control. The recommended adult starting dose should be reduced by 50% (for example a total daily dose of 10mg orally in opioid naïve patients), and each patient should be titrated to adequate pain control according to their clinical situation.

Patients with mild hepatic impairment should be treated with caution. The lowest dose should be given with careful titration to pain control. The recommended adult starting dose should be reduced by 50% (for example a total daily dose of 10mg orally in opioid naïve patients), and each patient should be titrated to adequate pain control according to their clinical situation.

May reduce the analgesic effect of oxycodone and/or precipitate withdrawal symptoms.

Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine.

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose.

Examples: cyclobenzaprine, metaxalone.

Use with caution in patients with diseases of the biliary tract.

Use with caution in patients with constipation.

Use with caution in patients with toxic psychosis.

Use with caution in patients with inflammatory bowel disorders.

Use with caution in patients with prostatic hypertrophy.

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), oxycodone may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with oxycodone.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of oxycodone in patients with impaired consciousness or coma.

Risks for opioid addiction, abuse, or misuse are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as oxycodone, but use in such patients necessitates intensive counseling about the risks and proper use of oxycodone along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose.

Use with caution in patients with psychological dependence [addiction], abuse profile or alcoholism.

Use with caution in patients with adrenocortical insufficiency or Addison’s disease.

As with all narcotics, a reduction in dosage may be advisable in hypothyroidism.

Use with caution in patients with myxedema.

Use with caution in patients with hypotension.

Use with caution in patients with sleep apnoea. Opioid may cause worsening of pre-existing sleep apnoea.

Use with caution in patients with pancreatitis.

Use with caution in patients with hypovolaemia.

Use with caution in patients with delirium tremens.

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery

Opioids cross the 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 the neonate. Oxycodone is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including oxycodone, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m² basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m² basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m² basis).

Risk Summary

Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. The lactation studies did not assess breastfed infants for potential adverse reactions. Νo information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production.

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

Clinical Considerations

Monitor infants exposed to οxycodone 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.

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of oxycodone hydrochloride have not been conducted.

Mutagenesis

Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) and in an assay for chromosomal aberrations (in vivo mouse bone marrow micronucleus assay).

Impairment of Fertility

Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

Oxycodone may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of oxycodone and know how they will react to the medication.

Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Tolerance and Dependence below). Constipation may be prevented with an appropriate laxative. If nausea and vomiting are troublesome oxycodone may be combined with an anti-emetic.

The undesirable effects listed below are classified by body system according to their incidence (common or uncommon). The following frequencies are basis for assessing undesirable effects: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10000 to <1/1000), Very Rare (<1/10000), Not Known (cannot be estimated from the available data).

Common adverse drug reactions have an incidence of 21% and uncommon adverse drug experiences have an incidence of <1%.

Tolerance and Dependence

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of oxycodone capsules may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increase blood pressure, respiratory rate or heart rate.

The development of psychological dependence (addiction) to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of psychological dependence (addiction) in chronic pain patients.

Oxycodone should be used with particular care in patients with a history of alcohol and drug abuse.

Drug dependence

Repeated use of oxycodone can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient’s individual risk factors, dosage, and duration of opioid treatment.

Paediatric population

The frequency, type and severity of adverse reactions in adolescents (12 to 18 years of age) appear similar to those in adults.

Overall, the safety data obtained with oxycodone in clinical, pharmacodynamic and pharmacokinetic studies demonstrate that oxycodone is well tolerated in paediatric patients with only minor adverse events affecting mainly the gastrointestinal and nervous system. All of the adverse events reported were consistent with the known safety profile of oxycodone as well as of other comparable strong opioids.

There are no clinical trial data on longer term use in children aged 12 to 18 years.