TARGINIQ ER (Page 8 of 11)

8.6 Hepatic Impairment

A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with hepatic impairment. Naloxone concentrations were affected to a higher degree than oxycodone. When administering TARGINIQ ER to patients with mild hepatic impairment, a dosage adjustment is recommended [see Dosage and Administration (2.4)]. 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 naloxone. TARGINIQ ER is contraindicated in patients with moderate and severe hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with renal impairment. Naloxone concentrations were affected to a higher degree than oxycodone. When administering TARGINIQ ER to patients with renal impairment, a dosage reduction is recommended [see Dosage and Administration (2.5)]. 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 naloxone. As patients with severe renal impairment may be at greater risk for opioid withdrawal-related adverse events, consider using alternative products without naloxone [see Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

TARGINIQ ER contains oxycodone, a Schedule II controlled substance.

9.2 Abuse

TARGINIQ ER contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and tapentadol. TARGINIQ 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, 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 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 addicts. In addition, abuse of opioids can occur in the absence of true addiction.

TARGINIQ 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of TARGINIQ ERTARGINIQ ER is for oral use only. Abuse of TARGINIQ ER poses a risk of overdose and death. The risk is increased with concurrent use of TARGINIQ ER with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved TARGINIQ ER enhances drug release and increases the risk of overdose and death.

If TARGINIQ ER tablets are crushed and administered via intranasal or intravenous routes, the resulting systemic naloxone concentrations are much higher and can induce a severe withdrawal syndrome in opioid-dependent individuals. Cases have been reported to the international drug safety database that involved attempts to manipulate the product for injection or insufflation, which resulted in withdrawal symptoms. In the majority of these cases, emergency attention was required.

With parenteral abuse, the inactive ingredients in TARGINIQ ER 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

In Vitro Testing

In vitro physical and chemical tablet manipulation studies were performed to evaluate the success of different extraction methods in defeating the controlled-release formulation of TARGINIQ ER and separating the oxycodone component from naloxone, a potent opioid antagonist. Laboratory test data demonstrate that TARGINIQ ER can be crushed and dissolved in solution. However, complete separation or complete inactivation of naloxone from oxycodone was not achieved despite using various techniques and conditions.

Clinical Abuse Potential Studies

In the clinical abuse potential studies described below, drug-liking was measured on a bipolar drug liking scale of 0 to 100 where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking and 100 represents maximum liking. Response to whether the subject would take the study drug again was measured on a unipolar scale of 0 to 100 where 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”). Response to subjective feeling of getting “high” was measured on a unipolar scale of 0 to 100, where 0 represents “definitely not” and 100 represents “definitely so”.

Study in Non-Dependent, Opioid Abusers (Intranasal (IN) Administration)

In a randomized, double-blind, placebo- and active-controlled, 3-period crossover pharmacodynamic study, 23 non-dependent, opioid abusers with moderate experience with opioids received IN administered TARGINIQ ER 40 mg/20 mg (finely crushed tablets), oxycodone HCl 40 mg powder (active control), and placebo treatments.

IN administration of finely crushed TARGINIQ ER was associated with statistically significant lower maximum drug liking scores (p < 0.001) and statistically significant lower maximum scores for take drug again (p < 0.001), compared to powdered oxycodone HCl, and was associated with similar mean and median maximum scores for drug liking and take drug again, compared to placebo treatment, as summarized in Table 6.

Table 6. Summary of Maximum Drug Liking (Emax ) and Take Drug Again (Emax ) Following Intranasal (IN) Administration of TARGINIQ ER, Oxycodone, and Placebo in Non-Dependent, Opioid Abusers (N=23)
VAS: visual analog scale
SE: standard error
* Drug Liking Question text: “At this moment, my liking for this drug is”; scale: 0 = maximum disliking, 50 = neither liking nor disliking (neutral response), 100 = maximum liking.
**Take Drug Again Question text: “I would take this drug again”; scale: 0 = definitely not, 100 = definitely so.
VASTARGINIQ ER 40 mg/20 mg(finely crushed)Oxycodone HCl 40 mg(powdered)Placebo(lactose powder)
Drug Liking*Mean (SE)59.1 (2.8)94.8 (2.2)53.2 (2.1)
Median (Range)51 (50-100)100 (61-100)51 (50-100)
Take Drug Again**Mean (SE)42.6 (6.4)93.6 (2.3)30.7 (6.1)
Median (Range)50.0 (0-100)100 (62-100)50 (0-100)

Figure 1 demonstrates a comparison of maximum drug liking for finely crushed TARGINIQ ER compared to powdered oxycodone HCl in subjects who received both treatments. The Y-axis represents the percent of subjects attaining a percent reduction in maximum drug liking for TARGINIQ ER vs. oxycodone HCl powder greater than or equal to the value on the X-axis. Among non-dependent, opioid drug abusers, 78% (n = 18) of subjects had a reduction of at least 30% in maximum drug liking with TARGINIQ ER compared to oxycodone HCl, and approximately 74% (n = 17) of subjects had a reduction of at least 50% in maximum drug liking with TARGINIQ ER compared to oxycodone HCl.

Figure 1. Percent Reduction in Maximum Drug Liking for Finely Crushed TARGINIQ ER 40 mg/20 mg vs. Powdered Oxycodone HCl 40 mg Following Intranasal Administration in Non-Dependent Opioid Abusers

figure-1
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Study in Non-Dependent, Opioid Abusers (Intravenous (IV) Administration) In a randomized, double-blind, placebo- and active-controlled, 3-period crossover pharmacodynamic study, 22 non-dependent, opioid abusers with moderate experience with opioids received intravenously administered 0.07 mg/kg oxycodone HCl and 0.035 mg/kg naloxone HCl solution (simulated version of TARGINIQ ER), oxycodone HCl (0.07 mg/kg solution; active control) and placebo (saline) treatments.

The intravenous administration of simulated TARGINIQ ER solution was associated with statistically significant lower maximum drug liking scores (p < 0.001) and statistically significant lower maximum scores for take drug again (p < 0.001), compared to oxycodone solution, and was associated with similar mean and median scores for drug liking and take drug again, compared to placebo treatment, as summarized in Table 7.

Table 7. Summary of Maximum Drug Liking (Emax ) and Take Drug Again Following IV Administration of Oxycodone HCl + Naloxone HCl (Simulated TARGINIQ ER Solution), Oxycodone HCl, and Placebo in Non-Dependent, Opioid Abusers (N=22)
VAS: visual analog scale
SE: standard error
* Drug Liking Question text: “At this moment, my liking for this drug is”; scale: 0 = maximum disliking, 50 = neither liking nor disliking (neutral response), 100 = maximum liking.
**Take Drug Again Question text: “I would take this drug again”; scale: 0 = definitely not, 100 = definitely so; Values obtained at 8 hours post dose.
VASOxycodone HCl/Naloxone HCl0.07/0.35 mg/kgOxycodone HCl0.07 mg/kgPlacebosaline (0.9% NaCl)
Drug Liking*Mean (SE)56.5 (2.8)96.4 (2.3)48.7 (2.3)
Median (Range)51 (50-100)100 (50-100)51.0 (0-53)
Take Drug Again**Mean (SE)37.0 (6.2)82.0 (6.0)34.5 (5.1))
Median (Range)50.0 (0-100)99.0 (0-100)50.0 (0-55)

Figure 2 demonstrates a comparison of maximum drug liking for simulated TARGINIQ ER solution compared to oxycodone HCl solution in subjects who received both treatments. Among non-dependent, opioid drug abusers, approximately 91% (n = 20) of subjects had a reduction of at least 50% in maximum drug liking with TARGINIQ ER compared to oxycodone solution.

Figure 2. Percent Reduction in Maximum Drug Liking for Oxycodone 0.07 mg/kg + Naloxone 0.035 mg/kg (Simulated TARGINIQ ER) vs. Oxycodone HCl 0.07 mg/kg Following Intravenous Administration in Non-Dependent, Opioid Abusers

figure-2
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Study in Opioid-Dependent Subjects In a randomized, double-blind, placebo- and positive-controlled, 4-period crossover pharmacodynamic study, 29 opioid-dependent, methadone-maintained subjects received orally administered TARGINIQ ER 60 mg/30 mg chewed and intact tablets, oxycodone HCl solution 60 mg (active control) and placebo (chewed and intact tablets and solution) treatments.

The oral administration of TARGINIQ ER, either chewed or intact, was associated with statistically significant lower maximum drug liking scores (p < 0.001) and statistically significant lower scores for take drug again (p < 0.001), compared to oxycodone solution, and was associated with similar mean and median maximum scores for drug liking and take drug again, compared to placebo treatment, as summarized in Table 8.

Table 8. Summary of High, Maximum Drug Liking (Emax ), and Take Drug Again Following Oral Administration of TARGINIQ ER (Intact and Chewed), Oxycodone HCl solution, and Placebo in Opioid-Dependent Subjects (N=29)
VAS: visual analog scale
SE: standard error
* Drug Liking Question text: “At this moment, my liking for this drug is”; scale: 0 = maximum disliking, 50 = neither liking nor disliking (neutral response), 100 = maximum liking.
**Take Drug Again Question text: “I would take this drug again”; scale: 0 = definitely not, 100 = definitely so; Values obtained at 12 hours post dose.
***Getting High Question Text: “I am feeling high”; scale: 0 = definitely not, 100 = definitely so.
VASTARGINIQ ER60 mg/30 mg intact TARGINIQ ER60 mg/30 mg chewedOxycodone HClsolution 60 mgPlacebochewed and intact tablet, solution
Drug Liking*Mean (SE)54.7 (2.0)54.6 (3.2)77.9 (3.8)54.4 (2.1)
Median (Range)51.0 (50-99)51.0 (0-100)78.0 (50-100)51.0 (50-100)
Take Drug Again**Mean (SE)38.5 (5.7)32.6 (5.9)61.4 (5.9)41.5 (5.0)
Median (Range)50.0 (0-100)50.0 (0-100)50.0 (0-100)50.0 (0-100)
Getting High***Mean (SE)20.6 (5.1)27.7 (6.5)77.9 (5.0)20.6 (5.0)
Median (Range)1.0 (0-73)1.0 (0-100)86.0 (0-100)1.0 (0-82)

Figure 3 demonstrates a comparison of maximum drug liking (Emax ) for TARGINIQ ER either chewed or intact compared to oxycodone solution in subjects who received both treatments. Among opioid-dependent subjects, 69.0% (n = 20) had a reduction of at least 30%, and 65.5% (n = 19) of subjects had a reduction of at least 50% in maximum drug liking with chewed TARGINIQ ER tablets compared to oxycodone solution; 79.3% (n = 23) of subjects had a reduction at least 50% in maximum drug liking with intact TARGINIQ ER tablets compared to oxycodone solution.

Figure 3. Percent Reduction in Maximum Drug Liking for TARGINIQ ER 60 mg/30 mg Chewed or Intact vs. Oxycodone HCl 60 mg Solution Following Oral Administration in Opioid-Dependent Subjects

figure-3
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SummaryBased on the in vitro study results, it is expected that abuse of oxycodone from physically and chemically manipulated TARGINIQ ER tablets will be deterred by the inability to separate the two active components.

The data from the clinical abuse potential studies indicate that TARGINIQ ER has pharmacologic properties that are expected to reduce abuse via the intranasal and intravenous routes of administration. However, abuse of TARGINIQ ER by these routes is still possible.

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

TARGINIQ ER contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. TARGINIQ ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.1)].

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