Oxycodone extended-release

Table 4 includes clinically significant drug interactions with OXYCONTIN. Table 4: Clinically Significant Drug Interactions with OXYCONTIN Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of OXYCONTIN 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 OXYCONTIN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved [see Warnings and Precautions (5.6) ] .

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of OXYCONTIN until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.6) ] .

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXYCONTIN dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.

Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3) ] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required.

Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2 , 2.6) , Warnings and Precautions (5.2 , 5.3) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.

Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome . Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue OXYCONTIN 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 inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. Intervention: The use of OXYCONTIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of OXYCONTIN and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.3) ].

Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concomitantly with anticholinergic drugs.

CNS Depressants : Concomitant use may cause hypotension, profound sedation, respiratory depression, coma, and death. If coadministration is required and the decision to begin OXYCONTIN is made, start with 1/3 to 1/2 the recommended starting dosage, consider using a lower dosage of the concomitant CNS depressant, and frequently evaluate. ( 2.6 , 5.3 , 7 ) Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue OXYCONTIN if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with OXYCONTIN because they may reduce analgesic effect of OXYCONTIN or precipitate withdrawal symptoms.

( 5.15 , 7 ) Monoamine Oxidase Inhibitors (MAOIs) : Can potentiate the effects of morphine. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ] . There are no available data with OXYCONTIN in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there was no embryo-fetal toxicity when oxycodone hydrochloride was orally administered to rats and rabbits, during the period of organogenesis, at doses 1.3 to 40 times the adult human dose of 60 mg/day, respectively.

In a pre- and postnatal toxicity study, when oxycodone was orally administered to rats, there was transiently decreased pup body weight during lactation and the early post-weaning period at the dose equivalent to an adult dose of 60 mg/day. In several published studies, treatment of pregnant rats with oxycodone hydrochloride 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 Use of opioid analgesics for an extended period of time 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 [see Warnings and Precautions (5.4) ] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. OXYCONTIN is not recommended for use in women immediately prior…