Limitations of Use:

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see Warnings and Precautions (5.1)], reserve TROXYCA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• TROXYCA ER is not indicated as an as-needed (prn) analgesic.

2.1 Important Dosage and Administration Instructions

TROXYCA ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

TROXYCA ER 60 mg/7.2 mg and 80 mg/9.6 mg capsules, single doses of TROXYCA ER greater than 40 mg/4.8 mg, or a total daily dose greater than 80 mg/9.6 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
• Initiate the dosing regimen for each patient individually; taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy and following dosage increases with TROXYCA ER and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Instruct patients to swallow TROXYCA ER capsules whole [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving the pellets in TROXYCA ER capsules will result in uncontrolled delivery of oxycodone and can lead to overdose or death [see Warnings and Precautions (5.1)].

Instruct patients who are unable to swallow TROXYCA ER capsules to sprinkle the capsule contents on applesauce and immediately swallow without chewing [see Dosage and Administration (2.5)].

Administer TROXYCA ER orally every 12 hours.

2.2 Initial Dosing

2.3 Titration and Maintenance of Therapy

Individually titrate TROXYCA ER to a dosage that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving TROXYCA ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.

Patients who experience breakthrough pain may require a dosage increase of TROXYCA ER, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the TROXYCA ER dosage. Because steady-state plasma concentrations are achieved within 48 hours, the total daily dose of TROXYCA ER may be adjusted by 20 mg/2.4 mg every 2 to 3 days as needed based on efficacy, safety, and tolerability.

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

There are no well-controlled clinical studies evaluating the safety and efficacy with dosing more frequently than every 12 hours.

2.4 Discontinuation of TROXYCA ER

When a patient no longer requires therapy with TROXYCA ER, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue TROXYCA ER [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

2.5 Administration of TROXYCA ER

Instruct patients to swallow TROXYCA ER capsules intact. The capsules contain pellets that consist of oxycodone HCl and sequestered naltrexone HCl. The pellets in the capsules are not to be manipulated, i.e., crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of oxycodone [see Warnings and Precautions (5.1)]. Consuming TROXYCA ER capsules that have been altered by crushing, dissolving, or chewing the pellets can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals [see Warnings and Precautions (5.12)].

Alternatively, the contents of the TROXYCA ER capsules (pellets) may be sprinkled over applesauce and then swallowed. This method is appropriate only for patients able to reliably swallow the applesauce without chewing. Other foods have not been tested and should not be substituted for applesauce. Instruct the patient to:

• Open the capsule.
• Sprinkle the pellets onto a small amount of applesauce and swallow immediately without chewing.
• Rinse the mouth to ensure all pellets have been swallowed.
• Discard the empty capsule shell after the contents have been sprinkled on applesauce.

Do not administer TROXYCA ER pellets through a nasogastric or gastric tube.

5.1 Addiction, Abuse, and Misuse

TROXYCA ER contains oxycodone, a Schedule II controlled substance. As an opioid, TROXYCA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As extended-release products such as TROXYCA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed TROXYCA ER and in those who obtain the drug illicitly. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing TROXYCA ER, and monitor all patients receiving TROXYCA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) 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 TROXYCA ER, but use in such patients necessitates intensive counseling about the risks and proper use of TROXYCA ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of TROXYCA ER by cutting, breaking, chewing, crushing, or dissolving the pellets in TROXYCA ER and then swallowing, snorting or injecting will result in the uncontrolled delivery of the oxycodone and can result in overdose and death [see Overdosage (10)]. Misuse or abuse of TROXYCA ER by these methods may also release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals [see Warnings and Precautions (5.12)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing TROXYCA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of TROXYCA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of TROXYCA ER.

To reduce the risk of respiratory depression, proper dosing and titration of TROXYCA ER are essential [see Dosage and Administration (2)]. Overestimating the TROXYCA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of TROXYCA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.

5.3 Neonatal Opioid Withdrawal Syndrome

Prolonged use of TROXYCA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of TROXYCA ER with a CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of TROXYCA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in TROXYCA ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using TROXYCA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in TROXYCA ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of TROXYCA ER until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of TROXYCA ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using TROXYCA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

5.5 Risks Due to Interactions with Central Nervous System Depressants

Hypotension, profound sedation, respiratory depression, coma, and death may result if TROXYCA ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids).

When considering the use of TROXYCA ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin TROXYCA ER is made, start with a lower dosage of TROXYCA ER, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7)].

5.6 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of TROXYCA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

5.7 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.8 Severe Hypotension

TROXYCA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of TROXYCA ER. In patients with circulatory shock, TROXYCA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of TROXYCA ER in patients with circulatory shock.

5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

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), TROXYCA ER 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 TROXYCA ER.

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

5.10 Risks of Use in Patients with Gastrointestinal Conditions

TROXYCA ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The oxycodone in TROXYCA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.11 Increased Risk of Seizures in Patients with Seizure Disorders

The oxycodone in TROXYCA ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during TROXYCA ER therapy.

5.12 Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including TROXYCA ER. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Consuming TROXYCA ER that has been altered by crushing, chewing, or dissolving the pellets can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals. Symptoms of withdrawal usually appear within five minutes of ingestion of naltrexone, can last for up to 48 hours, and can include mental status changes, restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Significant fluid losses from vomiting and diarrhea can require intravenous fluid administration.

When discontinuing TROXYCA ER, gradually taper the dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue TROXYCA ER [see Drug Abuse and Dependence (9.3)].

5.13 Risks of Driving and Operating Machinery

TROXYCA ER 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 TROXYCA ER and know how they will react to the medication [see Patient Counseling Information (17)].

5.14 Laboratory Tests and Monitoring

Naltrexone does not interfere with thin-layer, gas-liquid, or high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone, oxycodone, or quinine in the urine. Naltrexone may or may not interfere with enzymatic methods for the detection of opioids depending on the sensitivity and specificity of the test. Consult the test manufacturer for details.

Not every urine drug test for "opioids" or "opiates" detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified "cut-off" value as "negative". Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results.

6.1 Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In controlled and uncontrolled studies, the most common adverse reactions were nausea, constipation, vomiting, headache, and somnolence. The most common adverse reactions leading to discontinuation (≥1% in any of the treatment phases) were nausea, constipation, vomiting, somnolence, headache, fatigue, and dizziness.

In a randomized, placebo-controlled, double-blind study in subjects with moderate-to-severe chronic low back pain, 410 subjects received TROXYCA ER. This study utilized an enriched enrollment with a randomized withdrawal design in which subjects were titrated to effect on open-label TROXYCA ER for up to 42 days. Once their pain was controlled, 280 subjects were randomized to and received active treatment with TROXYCA ER (146 subjects) or were tapered off TROXYCA ER using a double-dummy design and treated with placebo (134 subjects) for 12 weeks.

Adverse reactions reported in ≥2% of subjects receiving TROXYCA ER in either the titration phase or maintenance phase of the placebo-controlled study are presented in Table 2.

An additional 395 subjects received at least one dose of TROXYCA ER in an open-label, 12-month safety study of subjects with moderate-to-severe chronic non-cancer pain. In this study, 193 subjects received TROXYCA ER for at least 6 months and 105 subjects received TROXYCA ER for approximately 12 months.

Adverse reactions reported in ≥2% of subjects of the 12-month open-label safety study are presented in Table 3.

6.2 Postmarketing Experience

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.

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 and pharyngeal edema: Anaphylaxis and pharyngeal edema have been reported with ingredients contained in TROXYCA ER.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Myocardial ischemia and ventricular fibrillation: Myocardial ischemia and ventricular fibrillation have been reported with oxycodone overdose.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of TROXYCA ER in patients less than 18 years of age have not been established.

8.5 Geriatric Use

The pharmacokinetics of TROXYCA ER have not been investigated in elderly patients (≥65 years) although such patients were included in clinical studies. Clinical studies with TROXYCA ER did not include sufficient numbers of subjects aged 65 and older to determine if they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

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, concomitant disease, and use of 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 TROXYCA ER slowly in geriatric patients [see Warnings and Precautions (5.6)].

This drug 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.

8.6 Hepatic Impairment

Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Naltrexone is sequestered in the TROXYCA ER capsules and is not intended to be released when TROXYCA ER is used as directed. However, measurable naltrexone plasma concentrations have been observed in some patients in clinical trials with TROXYCA ER [see Clinical Pharmacology (12.3)]. An increase in naltrexone AUC in patients with compensated and decompensated liver cirrhosis, compared with subjects with normal liver function, has been reported [see Clinical Pharmacology (12.3)]. These data also suggest that alterations in naltrexone bioavailability are related to liver disease severity.

Dose initiation of TROXYCA ER should follow a conservative approach in patients with hepatic impairment. In patients with hepatic impairment, there is a potential for differential increase in naltrexone exposure compared to oxycodone exposure. Hence, when administering TROXYCA ER to patients with hepatic impairment, monitor patients closely for signs of central nervous system or respiratory depression due to elevated levels of oxycodone and for signs of withdrawal due to elevated levels of naltrexone and adjust the dose based on the clinical response.

8.7 Renal Impairment

Elimination of oxycodone is reported to be impaired in patients with renal impairment.

Although naltrexone is sequestered in the TROXYCA ER formulations, measurable naltrexone plasma concentrations have been observed in some patients in clinical trials with TROXYCA ER [see Clinical Pharmacology (12.3)]. Since naltrexone and its primary metabolite are excreted primarily in urine, their plasma concentrations may be increased in patients with renal impairment.

Dose initiation of TROXYCA ER should follow a conservative approach in patients with renal impairment. In patients with renal impairment, there is a potential for differential increase in naltrexone exposure compared to oxycodone exposure. Hence, when administering TROXYCA ER to patients with renal impairment, monitor patients closely for signs of central nervous system or respiratory depression due to elevated levels of oxycodone and for signs of withdrawal due to elevated levels of naltrexone and adjust the dose based on the clinical response.

8.8 Sex Differences

There are no clinically significant differences in oxycodone pharmacokinetics following oral administration of TROXYCA ER to males or females; therefore, no specific dosage adjustment is recommended for the initiation or maintenance of TROXYCA ER doses based on the sex of the patient [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

TROXYCA ER contains oxycodone, a Schedule II controlled substance.

9.2 Abuse

TROXYCA ER contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol. TROXYCA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since 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 to persons with substance use 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 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 persons with substance use disorders. In addition, abuse of opioids can occur in the absence of true addiction.

TROXYCA ER, 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.

9.3 Dependence

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.

TROXYCA ER should not be abruptly discontinued [see Dosage and Administration (2.4)]. If TROXYCA ER 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, 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)].

Clinical Presentation

Acute overdosage 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, noncardiogenic 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.

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 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 reversal would be expected to be less than the duration of action of oxycodone in TROXYCA ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. TROXYCA ER will continue to release oxycodone, with systemic exposures of oxycodone for up to 48 hours after administration, necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be administered as directed in the product's prescribing information.

In an individual physically dependent on opioids, administration of the 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 begin with care and by titration with smaller than usual doses of the antagonist.

The sequestered naltrexone HCl in TROXYCA ER has no role in the treatment of opioid overdose.

Oxycodone Hydrochloride

The chemical name of oxycodone HCl is 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride. The empirical formula is C18H21NO4∙HCl and its molecular weight is 351.82.

Oxycodone HCl is a white to off-white, fine powder. It has a solubility of 0.20 g/mL at pH 6. Its structural formula is:

Naltrexone Hydrochloride

The chemical name of naltrexone HCl is (5α)-17-(Cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride. The empirical formula is C20H23NO4∙HCl and its molecular weight is 377.86.

Naltrexone HCl is a white to slightly off-white powder that is soluble in water. Its structural formula is:

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The analgesic activity of TROXYCA ER is primarily due to the parent drug oxycodone. TROXYCA ER is designed to provide delivery of oxycodone over 12 hours.

Chewing, crushing or dissolving the pellets within the TROXYCA ER capsules impairs the extended-release delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone as well as a potentially complete release of sequestered naltrexone.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Bottle count for each of these strengths is 100.
Store at 25°C (77°F); excursions permitted between 15° and 30°C (59° and 86°F).
Dispense in tight (USP), light-resistant, child-resistant containers.

Addiction, Abuse, and Misuse

Inform patients that the use of TROXYCA ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share TROXYCA ER with others and to take steps to protect TROXYCA ER 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 TROXYCA ER 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.

Accidental Ingestion

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 TROXYCA ER securely and to dispose of unused TROXYCA ER by flushing the capsules down the toilet.

Interactions with Alcohol and Other CNS Depressants

Inform patients that potentially serious additive effects may occur if TROXYCA ER is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a healthcare provider [see Warnings and Precautions (5.5)].

Serotonin Syndrome

Inform patients that TROXYCA ER 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 physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that TROXYCA ER 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

Instruct patients how to properly take TROXYCA ER, including the following:

• Swallow TROXYCA ER capsules whole or sprinkle the capsule contents on applesauce and then swallow immediately without chewing [see Dosage and Administration (2.1)].
• Do not crush, chew, or dissolve the pellets contained in the capsules due to a risk of fatal oxycodone overdose or naltrexone precipitated withdrawal symptoms in opioid-dependent individuals [see Dosage and Administration (2.1)].
• Use TROXYCA ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.2)].
• Do not discontinue TROXYCA ER without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration (2.4)].

Hypotension

Inform patients that TROXYCA ER may cause 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)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in TROXYCA ER. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Lactation

Advise patients that breastfeeding is not recommended during treatment with TROXYCA ER [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

Driving or Operating Heavy Machinery

Inform patients that TROXYCA ER 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)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)].

Disposal of Unused TROXYCA ER

Advise patients to flush the unused capsules down the toilet when TROXYCA ER is no longer needed.