Troxyca ER

Troxyca ER is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

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.

Troxyca ER is available in 6 strengths as an extended-release hard gelatin capsule filled with common pellets as noted below:

Controlled Substance

Troxyca ER contains oxycodone, a Schedule II controlled substance.

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.

Risks Specific to Abuse of Troxyca ER

Troxyca ER is for oral use only. Abuse of Troxyca ER poses a risk of overdose and death. This risk is increased with concurrent abuse of Troxyca ER with alcohol and other central nervous system depressants. Cutting, breaking, chewing, crushing, or dissolving the pellets in Troxyca ER and then swallowing, snorting or injecting will result in uncontrolled delivery of the oxycodone and increases the risk of overdose and death. The sequestered naltrexone HCl in Troxyca ER is intended to have no clinical effect when Troxyca ER is taken as directed; however, if the capsules are crushed or chewed, up to 100% of the sequestered naltrexone HCl dose could be released, equivalent to an immediate-release (IR) naltrexone HCl oral solution of the same dose. In opioid-tolerant individuals, the absorption of naltrexone HCl may increase the risk of precipitating withdrawal.

Due to the presence of talc as one of the excipients in Troxyca ER, parenteral abuse can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Abuse Deterrence Studies

Troxyca ER is formulated with a sequestered opioid antagonist, naltrexone HCl, which is released with manipulation by crushing.

In Vitro Testing

In vitro laboratory tests were performed to evaluate the effect of different physical and chemical conditions intended to defeat the extended-release formulation. When Troxyca ER is crushed and mixed in a variety of solvents, both oxycodone HCl and naltrexone HCl are simultaneously extracted.

Clinical Abuse Potential Studies

Two randomized, double-blind active- and placebo-controlled studies were conducted in non-dependent opioid abusers to characterize the abuse potential of oral or intranasal administration of Troxyca ER following physical manipulation. A third randomized, double-blind, single-dose, placebo and active-controlled study was conducted with IV administration of simulated crushed Troxyca ER. For these studies, Drug Liking was measured on a bipolar 100-point Visual Analog Scale (VAS) where 0 represents maximum disliking, 50 represents a neutral response (neither like nor dislike), and 100 represents maximum liking. Response to whether the subject would Take Drug Again was measured on a bipolar 100-point VAS where 0 represents strongest negative response (e.g., 'definitely would not take drug again'), 50 represents a neutral response, and 100 represents the strongest positive response (e.g., 'definitely would take drug again').

The pharmacokinetic profiles of oxycodone HCl and naltrexone HCl were also determined in these abuse potential studies. When Troxyca ER was crushed and administered orally (40 mg/4.8 mg and 60 mg/7.2 mg doses) or intranasally (30 mg/3.6 mg doses), oxycodone HCl and naltrexone HCl were both absorbed rapidly with median time-to-peak concentration (Tmax) values of approximately 0.6–1 hour and 0.6 hours, respectively, following oral administration and 1.6 hours and 0.3 hours, respectively, following intranasal administration.

Oral Abuse Potential Study

In this study, 31 non-dependent, recreational opioid abusers received all six treatments by the oral route: crushed 40 mg/4.8 mg Troxyca ER in solution, crushed 40 mg immediate-release (IR) oxycodone HCl in solution, intact 60 mg/7.2 mg Troxyca ER, crushed 60 mg/7.2 mg Troxyca ER in solution, crushed 60 mg IR oxycodone HCl in solution, and placebo. When 40 mg/4.8 mg Troxyca ER and 60 mg/7.2 mg Troxyca ER were crushed and taken orally, the geometric mean (SD) values for naltrexone HCl Cmax were 1074 (1463) pg/mL and 1810 (2450) pg/mL respectively; the AUC0–2h values were 1217 (1471) and 2010 (1839) pg∙h/mL, and the AUCinf values were 2877 (2834) pg∙h/mL and 4695 (3714) pg∙h/mL, respectively.

Oral administration of crushed 40 mg/4.8 mg Troxyca ER was associated with statistically significantly lower means and medians for Drug Liking and Take Drug Again Emax compared with crushed 40 mg IR oxycodone HCl. Oral administration of crushed 60 mg/7.2 mg Troxyca ER was associated with statistically significantly lower means and medians for Drug Liking Emax compared to crushed 60 mg IR oxycodone HCl. The mean and median Take Drug Again Emax for crushed 60 mg/7.2 mg Troxyca ER compared with crushed 60 mg IR oxycodone HCl was numerically lower; however, this finding did not reach statistical significance. The results from this study are summarized in Table 6.

Among the 31 subjects who received both Troxyca ER and IR oxycodone by the oral route, 74% (23) and 77% (24) experienced some reduction in Drug Liking Emax with crushed 40 mg/4.8 mg Troxyca ER and crushed 60 mg/7.2 mg Troxyca ER, respectively, compared to crushed IR oxycodone, while 26% (8) and 23% (7) of subjects had no reduction in Drug Liking Emax for crushed 40 mg/4.8 mg Troxyca ER and crushed 60 mg/7.2 mg Troxyca ER, respectively, compared to crushed IR oxycodone. With crushed 40 mg/4.8 mg Troxyca ER, 65% (20) of subjects had at least a 30% reduction and 55% (17) of subjects had at least a 50% reduction in Drug Liking Emax compared to crushed 40 mg IR oxycodone. With crushed 60 mg/7.2 mg Troxyca ER, 61% (19) of subjects had at least a 30% reduction and 45% (14) of subjects had at least a 50% reduction in Drug Liking Emax compared to crushed 60 mg IR oxycodone.

Intranasal Abuse Potential Study

In this study, 27 non-dependent, recreational opioid abusers with experience with intranasal administration of opioids received all four treatments by the intranasal route: crushed 30 mg/3.6 mg Troxyca ER, crushed 30 mg IR oxycodone HCl, crushed placebo sugar spheres and crushed placebo lactose tablets. Placebo sugar spheres and placebo lactose tablets were weight matched to Troxyca ER or IR oxycodone HCl. When Troxyca ER was crushed and taken intranasally, the geometric mean (SD) values for naltrexone HCl Cmax, AUC0–2h, and AUCinf were 4372 (1409) pg/mL, 5481 (1472) pg∙hr/mL, and 10710 (3213) pg∙hr/mL, respectively.

Intranasal administration of crushed Troxyca ER was associated with statistically significantly lower means and medians for Drug Liking and Take Drug Again Emax compared with crushed IR oxycodone HCl (summary statistics for Drug Liking and Take Drug Again in Table 7).

Among 27 subjects who received both Troxyca ER and IR oxycodone by the intranasal route, 93% (25) experienced some reduction in Drug Liking Emax with crushed Troxyca ER compared to crushed IR oxycodone, while 7% (2) of subjects had no reduction in Drug Liking Emax for crushed Troxyca ER compared to crushed IR oxycodone. With crushed Troxyca ER 93% (25) of subjects had at least a 30% reduction in Drug Liking Emax and 85% (23) of subjects had at least a 50% reduction in Drug Liking Emax compared to crushed IR oxycodone.

Simulated IV Abuse Potential Study

This study in non-dependent recreational opioid abusers compared 20 mg IV oxycodone HCl in combination with 2.4 mg IV naltrexone HCl (to simulate parenteral use of crushed Troxyca ER) to 20 mg of IV oxycodone HCl and placebo; 29 subjects received all three treatments. These doses were based on the assumption of the complete release of both oxycodone HCl and naltrexone HCl upon crushing Troxyca ER. Intravenous administration of the combination of oxycodone HCl and naltrexone HCl was associated with statistically significantly lower mean and median Drug Liking and Take Drug Again Emax scores (median scores 51 and 50, respectively) compared with oxycodone alone (median scores 97 and 81, respectively). Among 29 subjects, 90% (26) experienced some reduction in Emax of Drug Liking with simulated parenteral use of crushed Troxyca ER compared to IV oxycodone HCl, while 10% (3) of subjects had no reduction in Drug Liking Emax for simulated parenteral use of crushed Troxyca ER compared to IV oxycodone HCl.

Summary

The in vitro and pharmacokinetic data demonstrate that crushing Troxyca ER pellets results in the simultaneous release and absorption of oxycodone HCl and naltrexone HCl. These data along with results from the oral and intranasal human abuse potential studies indicate that Troxyca ER has properties that are expected to reduce abuse via the oral and intranasal routes. However, abuse of Troxyca ER by these routes is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of Troxyca ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

A human abuse potential study of intravenous oxycodone HCl and naltrexone HCl to simulate crushed Troxyca ER demonstrated lower Drug Liking and Take Drug Again Emax compared with oxycodone HCl alone. However, it is unknown whether these results with simulated crushed Troxyca ER predict a reduction in abuse by the IV route until additional postmarketing data are available.

Troxyca ER contains oxycodone HCl, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal and illicit, 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), Drug Abuse and Dependence (9.1)].

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)].

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 60793-536-01

Pfizer

TROXYCA® ER
(oxycodone hydrochloride
and naltrexone hydrochloride)
extended-release capsules

CII

80 mg/9.6 mg

THE PELLETS SHOULD NOT BE CHEWED, CRUSHED, OR DISSOLVED.

For use in opioid-tolerant patients only

100 Capsules
Rx only