Oxycontin Drug Information

Clinical Trial Experience Adult Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OXYCONTIN was evaluated in double-blind clinical trials involving 713 patients with moderate to severe pain of various etiologies. In open-label studies of cancer pain, 187 patients received OXYCONTIN in total daily doses ranging from 20 mg to 640 mg per day.

The average total daily dose was approximately 105 mg per day. OXYCONTIN may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock . The most common adverse reactions (>5%) reported by patients in clinical trials comparing OXYCONTIN with placebo are shown in Table 2 below: TABLE 2: Common Adverse Reactions (>5%) Adverse Reaction OXYCONTIN (n=227) Placebo (n=45) (%) (%) Constipation Nausea Somnolence Dizziness Pruritus Vomiting Headache Dry Mouth Asthenia - Sweating In clinical trials, the following adverse reactions were reported in patients treated with OXYCONTIN with an incidence between 1% and 5%: Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, gastritis General disorders and administration site conditions: chills, fever Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: twitching Psychiatric disorders: abnormal dreams, anxiety, confusion, dysphoria, euphoria, insomnia, nervousness, thought abnormalities Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups Skin and subcutaneous tissue disorders: rash Vascular disorders: postural hypotension The following adverse reactions occurred in less than 1% of patients involved in clinical trials: Blood and lymphatic system disorders: lymphadenopathy Ear and labyrinth disorders: tinnitus Eye disorders: abnormal vision Gastrointestinal disorders: dysphagia, eructation, flatulence, gastrointestinal disorder, increased appetite, stomatitis General disorders and administration site conditions: withdrawal syndrome (with and without seizures), edema, peripheral edema, thirst, malaise, chest pain, facial edema Injury, poisoning and procedural complications: accidental injury Investigations: ST depression Metabolism and nutrition disorders: dehydration Nervous system disorders: syncope, migraine, abnormal gait, amnesia, hyperkinesia, hypoesthesia, hypotonia, paresthesia, speech disorder, stupor, tremor, vertigo, taste perversion Psychiatric disorders: depression, agitation, depersonalization, emotional lability, hallucination Renal and urinary disorders: dysuria, hematuria, polyuria, urinary retention Reproductive system and breast disorders: impotence Respiratory, thoracic and mediastinal disorders: cough increased, voice alteration Skin and subcutaneous tissue disorders: dry skin, exfoliative dermatitis Clinical Trial Experience in Pediatric Patients 11 Years and Older The safety of OXYCONTIN has been evaluated in one clinical trial with 140 patients 11 to 16 years of age. The median duration of treatment was approximately three weeks.

The most frequently reported adverse events were vomiting, nausea, headache, pyrexia, and constipation. Table 3 includes a summary of the incidence of treatment emergent adverse events reported in ≥5% of patients. Table 3: Incidence of Adverse Reactions Reported in ≥ 5.0% Patients 11 to 16 Years System Organ Class Preferred Term 11 to 16 Years (N=140) n (%) Any Adverse Event >= 5% 71 GASTROINTESTINAL DISORDERS 56 Vomiting 30 Nausea 21 Constipation 13 Diarrhea 8 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 32 Pyrexia 15 METABOLISM AND NUTRITION DISORDERS 9 Decreased appetite 7 NERVOUS SYSTEM DISORDERS 37 Headache 20 Dizziness 12 SKIN AND SUBCUTANEOUS TISSUE DISORDERS 23 Pruritus 8 The following adverse reactions occurred in a clinical trial of OXYCONTIN in patients 11 to 16 years of age with an incidence between ≥1.0% and < 5.0%. Events are listed within each System/Organ Class.

Blood and lymphatic system disorders: febrile neutropenia, neutropenia Cardiac disorders: tachycardia Gastrointestinal disorders: abdominal pain, gastroesophageal reflux disease General disorders and administration site conditions: fatigue, pain, chills, asthenia Injury, poisoning, and procedural complications: procedural pain, seroma Investigations: oxygen saturation decreased, alanine aminotransferase increased, hemoglobin decreased, platelet count decreased, neutrophil count decreased, red blood cell count decreased, weight decreased Metabolic and nutrition disorders: hypochloremia, hyponatremia Musculoskeletal and connective tissue disorders: pain in extremity, musculoskeletal pain Nervous system disorders: somnolence, hypoesthesia, lethargy, paresthesia Psychiatric disorders: insomnia, anxiety, depression, agitation Renal and urinary disorders: dysuria, urinary retention Respiratory, thoracic, and mediastinal disorders: oropharyngeal pain Skin and subcutaneous tissue disorders: hyperhidrosis, rash

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of extended-release oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abuse, addiction, aggression, amenorrhea, cholestasis, completed suicide, death, dental caries, increased hepatic enzymes, hyperalgesia, hypogonadism, hyponatremia, ileus, intentional overdose, mood altered, muscular hypertonia, overdose, palpitations (in the context of withdrawal), seizures, suicidal attempt, suicidal ideation, syndrome of inappropriate antidiuretic hormone secretion, and urticaria.

In addition to the events listed above, the following have also been reported, potentially due to the swelling and hydrogelling property of the tablet: choking, gagging, regurgitation, tablets stuck in the throat and difficulty swallowing the tablet. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis : Anaphylaxis has been reported with ingredients contained in OXYCONTIN. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids.

Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse, respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months.

New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.

Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

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 . 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. 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 , 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. 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 . 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 . 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). 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. 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. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue OXYCONTIN if serotonin syndrome is suspected.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with OXYCONTIN because they may reduce analgesic effect of OXYCONTIN or precipitate withdrawal symptoms. 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.

Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome . 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. 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 . 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 to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including OXYCONTIN, 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Pregnant rats were treated with 0.5, 2, 4, and 8 mg/kg oxycodone hydrochloride (0.08, 0.3, 0.7, and 1.3 times the human daily dose of 60 mg/day, respectively based on a mg/m 2 basis) during the period of organogenesis.

Oxycodone did not cause adverse effects to the fetus at exposures up to 1.3 times the human dose of 60 mg/day. The high dose produced maternal toxicity characterized by excessive gnawing on forelimbs and decreased body weight gain. Pregnant rabbits were treated with 1, 5, 25, and 125 mg/kg oxycodone hydrochloride (0.3, 2, 8, and 40 times the human daily dose of 60 mg/day, respectively, based on a mg/m 2 basis) during the period of organogenesis.

Oxycodone did not cause adverse effects to the fetus at exposures up to 40 times the human dose of 60 mg/day. The 25 mg/kg and 125 mg/kg doses high doses produced maternal toxicity characterized by decreased food consumption and body weight gain. Pregnant rats were treated with 0.5, 2, and 6 mg/kg oxycodone hydrochloride (0.08, 0.32, and 1 times the human daily dose of 60 mg/kg, respectively, based on a mg/m 2 basis) during the period of organogenesis through lactation.

Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by mothers given the highest dose used (6 mg/kg/day, equivalent to an adult human dose of 60 mg/day, on a mg/m 2 basis). However, body weight of these pups recovered. In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and 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 oral dose of 60 mg/day on a mg/m 2 basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/m 2 basis).

Pediatric Use The safety and efficacy of OXYCONTIN have been established in pediatric patients ages 11 to 16 years. Use of OXYCONTIN is supported by evidence from adequate and well-controlled trials with OXYCONTIN in adults as well as an open-label study in pediatric patients ages 6 to 16 years. However, there were insufficient numbers of patients less than 11 years of age enrolled in this study to establish the safety of the product in this age group.

The safety of OXYCONTIN in pediatric patients was evaluated in 155 patients previously receiving and tolerating opioids for at least 5 consecutive days with a minimum of 20 mg per day of oxycodone or its equivalent on the two days immediately preceding dosing with OXYCONTIN. Patients were started on a total daily dose ranging between 20 mg and 100 mg depending on prior opioid dose. The most frequent adverse events observed in pediatric patients were vomiting, nausea, headache, pyrexia, and constipation .

is contraindicated in patients with: Significant respiratory depression Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment Known or suspected gastrointestinal obstruction, including paralytic ileus Hypersensitivity (e.g., anaphylaxis) to oxycodone Significant respiratory depression Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment Known or suspected gastrointestinal obstruction, including paralytic ileus Hypersensitivity to oxycodone

Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene.

Because the duration of reversal is expected to be less than the duration of action of oxycodone in OXYCONTIN, carefully monitor the patient until spontaneous respiration is reliably reestablished. OXYCONTIN will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.