OXAYDO- oxycodone hydrochloride tablet
Egalet US Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use OXAYDO safely and effectively. See full prescribing information for OXAYDO.
OXAYDO® (oxycodone HCl) tablets for oral use only – CII
Initial U.S. Approval: 1950
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
OXAYDO is an opioid agonist indicated for the management of acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (1)
Limitations of Use (1)
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve OXAYDO for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mg and 7.5 mg oxycodone HCl (3)
WARNINGS AND PRECAUTIONS
Most common adverse reactions (incidence ≥3%) were nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Egalet US Inc. at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
5.6 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
Addiction, Abuse, and Misuse
OXAYDO exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing OXAYDO, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of OXAYDO. Monitor for respiratory depression, especially during initiation of OXAYDO or following a dose increase [see Warnings and Precautions (5.2)].
Accidental ingestion of even one dose of OXAYDO, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of OXAYDO during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. 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 [see Warnings and Precautions (5.3)].
Cytochrome P450 3A4 Interaction
The concomitant use of OXAYDO with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving OXAYDO and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.4), Drug Interactions (7), Clinical Pharmacology (12.3)].
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5), Drug Interactions (7)].
OXAYDO must be swallowed whole. Take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)]. OXAYDO is not amenable to crushing and dissolution. Do not administer OXAYDO via nasogastric, gastric or other feeding tubes as it may cause obstruction of feeding tubes.
Selection of patients for treatment with OXAYDO should be governed by the same principles that apply to the use of other potent opioid analgesics. Opioid analgesics given on a fixed-dosage schedule have a narrow therapeutic index in certain patient populations, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension. Healthcare providers should individualize treatment in every case, using non-opioid analgesics, opioids and/or combination products when necessary, and chronic opioid therapy with drugs such as OXAYDO in a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Care Policy and Research, and the American Pain Society.
Patients with chronic pain may need to be dosed at the lowest dosage level that will achieve acceptable analgesia and tolerable adverse reactions, on an around-the-clock basis rather than on an as needed basis.
Conversion from Fixed-Ratio Oral Opioid/Non-Opioid Combinations
When converting patients from fixed-ratio opioid/non-opioid drug regimens to OXAYDO, determine whether or not to continue the non-opioid analgesic. Titrate the dose of OXAYDO in response to the level of analgesia and adverse reactions afforded by the dosing regimen regardless of whether the non-opioid is continued.
Conversion from Other Oral Opioid Therapy to OXAYDO
If a patient has been receiving opioid-containing medications prior to taking OXAYDO, factor the potency of the prior opioid relative to oxycodone into the selection of the total daily dose of oxycodone.
In converting patients from other opioids to OXAYDO, close observation and adjustment of dosage based upon the patient's response to OXAYDO is imperative.
Tablets: 5 mg and 7.5 mg of oxycodone HCl, USP:
|5 mg||Round, convex, white tablet, debossed “5” on one side, letter “O” on other side.|
|7.5 mg||Round, convex, white tablet, debossed “7.5” on one side, letter “O” on other side.|
The following serious adverse reactions are described, or described in greater detail, in other sections:
Because clinical trials are conducted under widely varying conditions, the 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 clinical practice.
Serious adverse reactions that may be associated with OXAYDO include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock [see Warnings and Precautions (5) and Overdosage (10)].
The common adverse reactions seen on initiation of therapy with OXAYDO are dose-dependent, and their frequency depends on the clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid therapy. The most frequent of the adverse reactions include nausea, constipation, vomiting, headache, and pruritus.
The frequency of adverse reactions during initiation of opioid therapy may be minimized by careful individualization of starting dosage, slow titration and the avoidance of large rapid swings in plasma concentration of the opioid. Many of these adverse reactions will abate as therapy is continued and some degree of tolerance is developed, but others may be expected to remain throughout therapy.
In all patients for whom dosing information was available (n=191) from open-label and double-blind studies involving oxycodone, the following adverse reactions were recorded in oxycodone-treated patients with an incidence of ≥3%. In descending order of frequency they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.
The following adverse reactions occurred in less than 3% of patients involved in clinical trials with oxycodone:
Body as a Whole: abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis.
Cardiovascular: deep vein thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia.
Digestive: anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting.
Hematopoietic and Lymphatic: anemia and leukopenia.
Metabolism and Nutrition: edema, gout, hyperglycemia, iron deficiency anemia, and peripheral edema.
Musculoskeletal: arthralgia, arthritis, bone pain, myalgia, and pathological fracture.
Nervous System: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation.
Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis.
Skin and Appendages: herpes simplex, rash, sweating, and urticaria.
Special Senses: amblyopia.
Urogenital: urinary tract infection.
The following adverse reactions have been identified during post approval use of 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. These events include:
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 OXAYDO.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].
Table 1 includes clinically significant drug interactions with OXAYDO.
|Table 1: Clinically Significant Drug Interactions with OXAYDO|
|Inhibitors of CYP3A4 and CYP2D6|
The concomitant use of OXAYDO 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 OXAYDO and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXAYDO is achieved [see Warnings and Precautions (5.4)].
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.
If concomitant use is necessary, consider dosage reduction of OXAYDO 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 OXAYDO 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)|
The concomitant use of OXAYDO 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 (5.4)].
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 OXAYDO dosage until stable drug effects are achieved [see Dosage and Administration (2.3)]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXAYDO dosage reduction and monitor for signs of respiratory depression.|
|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, increases the risk of 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. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].|
|Examples:||Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.|
|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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXAYDO 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), monoamine oxidase (MAO) 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)].|
The use of OXAYDO is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
|Examples:||Phenelzine, tranylcypromine, linezolid|
|Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics|
|Clinical Impact:||May reduce the analgesic effect of OXAYDO and/or precipitate withdrawal symptoms.|
|Intervention:||Avoid concomitant use.|
|Examples:||Butorphanol, nalbuphine, pentazocine, buprenorphine|
|Clinical Impact:||Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.|
|Intervention:||Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXAYDO and/or the muscle relaxant as necessary.|
|Clinical Impact:||Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.|
|Intervention:||Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.|
|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:||Monitor patients for signs of urinary retention or reduced gastric motility when OXAYDO is used concomitantly with anticholinergic drugs.|
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with OXAYDO in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies with oral administrations of oxycodone HCl 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 2-4% and 15-20%, respectively.
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. Lactation studies have not been conducted with OXAYDO, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with OXAYDO.
Monitor infants exposed to OXAYDO 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 breastfeeding is stopped.
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].
The safety, effectiveness, and pharmacokinetics of OXAYDO in pediatric patients below the age of 18 have not been established.
Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of OXAYDO slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)].
Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Follow a conservative approach to initiate dosing in patients with hepatic impairment. Monitor patients closely and adjust the dose based on clinical response [see Dosage and Administration (2.2)].
Information from oxycodone HCl indicates that patients with renal impairment had higher plasma concentrations of oxycodone than subjects with normal renal function. Use a conservative approach to initiate dosing in patients with renal impairment. Monitor patients closely and adjust the dose based on clinical response [see Dosage and Administration (2.2)].
OXAYDO contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol. OXAYDO can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in persons with substance abuse disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
OXAYDO, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of OXAYDO
OXAYDO is intended for oral use only. Abuse of OXAYDO poses a risk of overdose and death. The risk of overdose and death is increased with concurrent abuse of alcohol or other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
In a double-blind, active-comparator, crossover study in 40 non-dependent recreational opioid users, “drug liking” responses and single-dose safety of crushed OXAYDO tablets were compared with crushed immediate-release oxycodone tablets when subjects self-administered the drug intranasally. The presence of sequence effects resulted in questionable reliability of the second period data. First period data demonstrated small numeric differences in the median and mean drug liking scores, lower in response to OXAYDO than immediate-release oxycodone. Thirty percent of subjects exposed to OXAYDO responded that they would not take the drug again compared to 5% of subjects exposed to immediate-release oxycodone. Study subjects self-administering OXAYDO reported a higher incidence of nasopharyngeal and facial adverse events and a decreased ability to completely insufflate two crushed tablets within a fixed time period (21 of 40 subjects). The clinical significance of the difference in drug liking and difference in response to taking the drug again reported in this study has not yet been established. There is no evidence that OXAYDO has a reduced abuse liability compared to immediate-release oxycodone.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
OXAYDO should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.4)]. If OXAYDO is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].
Acute overdose with OXAYDO 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, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].
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 and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias may require advanced life-support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in OXAYDO, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist 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 antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
OXAYDO (oxycodone HCl) 5 mg and 7.5 mg tablets are an immediate-release opioid agonist intended for oral administration only.
Chemically, oxycodone HCl is 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one HCl, a white, odorless crystalline powder. Oxycodone HCl is soluble in water (1 g in 6 to 7 mL). The molecular weight of oxycodone HCl is 351.82. The molecular formula for oxycodone HCl is C18H21NO4•HCl, and the structure is:
The inactive ingredients in OXAYDO include: colloidal silicon dioxide NF; crospovidone NF; magnesium stearate NF; microcrystalline cellulose NF; polyethylene oxide NF; and sodium lauryl sulfate NF.
The tablets are round, convex, white and debossed with the strength (5 or 7.5) on one side and the letter “O” on the other side.
Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Effects on the Central Nervous System
Oxycodone produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating, and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2)].
Concentration–Adverse Reaction Relationships
There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].
The analgesic activity of OXAYDO is primarily due to the parent drug oxycodone.
The pharmacokinetics of oxycodone after OXAYDO administration are characterized by peak plasma concentrations occurring on average within 1.2 to 1.4 hours of the first dose under fasted conditions. Thereafter, oxycodone concentrations fall with an average terminal half-life ranging between 3-4 hours. OXAYDO is bioequivalent with oxycodone immediate-release tablets in the fasted state, with no differences identified in the time to peak exposure (Tmax) and terminal elimination half-life (T½) of oxycodone between administration of OXAYDO and oxycodone immediate-release tablets. Dose proportionality was established for OXAYDO at doses of 5 mg, 10 mg, and 15 mg (oxycodone HCl) based on proportional increases in oxycodone Cmax and AUC exposure levels.
The oral bioavailability of oxycodone is 60% to 87%. The high oral bioavailability of oxycodone (compared to other oral opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone compared to other oral opioids.
When administered with a high fat meal, mean AUC values are increased by 21% and peak concentrations are decreased by 14%. Food causes a delay in Tmax from 1.25 to 3.00 hours. These changes in oxycodone pharmacokinetics are not considered clinically relevant; therefore, OXAYDO can be taken without regard to food.
Following intravenous administration, the volume of distribution for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was approximately 45%. Oxycodone has been found in breast milk [see Use in Specific Populations (8.2)].
The total plasma clearance of oxycodone is 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone was 3.5 to 4 hours.
Oxycodone HCl is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known.
Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; and conjugated oxymorphone ≤14%. Both free and conjugated noroxycodone have been found in urine but not quantified.
Age: Geriatric Population
Information obtained for oxycodone indicates that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.
Information obtained for oxycodone support the lack of sex effect on the pharmacokinetics of oxycodone.
Information obtained for oxycodone indicates that patients with renal impairment had higher plasma concentrations of oxycodone than subjects with normal renal function [see Use in Specific Populations (8.7)].
Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment [see Use in Specific Populations (8.6)].
Drug Interaction Studies
CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the coadministration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively [see Warnings and Precautions (5.4) and Drug Interactions (7)].
A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively [see Warnings and Precautions (5.4) and Drug Interactions (7)].
Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with OXAYDO.
Long-term studies in animals to evaluate its carcinogenic potential of oxycodone have not been conducted.
Oxycodone 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.
OXAYDO (oxycodone HCl) 5 mg tablets are round, convex, white tablets debossed with the strength “5” on one side and the letter “O” on the other side and supplied as:
NDC 69344-113-11 Bottles of 100 tablets
OXAYDO 7.5 mg tablets are round, convex, white tablets debossed with the strength “7.5” on one side and the letter “O” on the other side and supplied as:
NDC 69344-213-11 Bottles of 100 tablets
Dispense in tight container as defined in the USP, with a child-resistant closure.
Store at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].
Protect from moisture.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addiction, Abuse, and Misuse
Inform patients that the use of OXAYDO, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share OXAYDO with others and to take steps to protect OXAYDO from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting OXAYDO or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store OXAYDO securely and to dispose of unused OXAYDO by flushing them down the toilet.
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if OXAYDO is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.5), Drug Interactions (7)].
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7)].
Inform patients to avoid taking OXAYDO while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking OXAYDO [see Drug Interactions (7)].
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.7)].
Important Administration Instructions
If patients have been receiving treatment with OXAYDO for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. Provide a dose schedule to help patients gradually discontinue the medication.
Inform patients that OXAYDO may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8)].
Inform patients that anaphylaxis has been reported with ingredients contained in OXAYDO. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].
Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2)].
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].
Driving or Operating Heavy Machinery
Inform patients that OXAYDO may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.13)].
Disposal of Unused OXAYDO
Advise patients to keep OXAYDO in a secure place out of the reach of children. When OXAYDO is no longer needed, the unused tablets should be destroyed by flushing them down the toilet.
Egalet US Inc.
Wayne, PA 19087
LBL #: 201.01
|This Medication Guide has been approved by the U.S. Food and Drug Administration.||Issued: 12/2016|
OXAYDO (ox Ā doe)
Important information about OXAYDO:
Do not take OXAYDO if you have:
Before taking OXAYDO, tell your healthcare provider if you have a history of:
Tell your healthcare provider if you are:
When taking OXAYDO:
While taking OXAYDO DO NOT:
The possible side effects of OXAYDO:
Get emergency medical help if you have:
These are not all the possible side effects of OXAYDO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
Distributed by: Egalet US Inc., Wayne, PA, 19087; for more information go to www.oxaydo.com or call 1-800-518-1084
oxycodone hydrochloride tablet
oxycodone hydrochloride tablet
|Labeler - Egalet US Inc. (079581441)|