2.1 Important Dosing and Administration Instructions

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

A single dose of TARGINIQ ER greater than 40 mg/20 mg or a total daily dose greater than 80 mg/40 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 (5.1)].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 with TARGINIQ ER and following dosage increases with TARGINIQ and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

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

TARGINIQ ER is administered orally every 12 hours.

2.2 Initial Dosage

Use of TARGINIQ ER as the First Opioid Analgesic (opioid-naïve patients)
Initiate treatment with TARGINIQ ER with one 10 mg/5 mg tablet orally every 12 hours.

Use of TARGINIQ ER in Patients who are not Opioid Tolerant (opioid non-tolerant patients)
The starting dosage for patients who are not opioid tolerant is TARGINIQ ER 10 mg/5 mg orally every 12 hours.
Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Conversion from Other Oral Oxycodone Formulations to TARGINIQ ER
Patients receiving other oral oxycodone formulations may be converted to TARGINIQ ER by administering one-half of the patient's total daily oral oxycodone dose as TARGINIQ ER every 12 hours.

Conversion from Other Opioids to TARGINIQ ER
Discontinue all other around-the-clock opioid drugs when TARGINIQ ER therapy is initiated.

There is inter-patient variability in the relative potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of TARGINIQ ER. It is safer to underestimate a patient’s 24-hour oral oxycodone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxycodone dosage and manage an adverse reaction due to an overdose.

In a TARGINIQ ER clinical trial with an open-label titration period, patients were converted from their prior opioid to TARGINIQ ER using both Table 1 and Table 2 below.

Consider the following when using the information in Table 1 and Table 2:

• These are not tables of equianalgesic doses. The conversion factors in Table 1 are only for the conversion from one of the listed oral opioid analgesics to the Equivalent Daily Oral Morphine Dose.
• The conversion factors in Table 2 are only for conversion from the calculated Equivalent Daily Oral Morphine Dose to TARGINIQ ER.
• The tables cannot be used to convert from TARGINIQ ER to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in a fatal overdose.

Convert patients from their previous opioid to TARGINIQ ER as follows:

1. Using Table 1, calculate the Equivalent Daily Oral Morphine Dose by multiplying the current total daily dose of each opioid by the appropriate Conversion Factor.
2. Using Table 2, determine the starting dose of TARGINIQ ER by reading across from the appropriate Equivalent Daily Dose of Oral Morphine range, rounding down, if necessary.

Example conversion from a single opioid to TARGINIQ ER:

Step 1: A patient receiving oxymorphone at a total daily dose of 10 mg would equate to an Equivalent Daily Oral Morphine Dose of 40 mg (10 mg x 4; Table 1).

Step 2: Based on Table 2, the starting dose is TARGINIQ ER 10 mg/5 mg every 12 hours.

• For patients on a regimen of more than one opioid, use Table 1 to calculate the Equivalent Daily Oral Morphine dose for each opioid and sum the totals, then use Table 2 to obtain the starting dose of TARGINIQ ER.
• Round down, if necessary, to the appropriate TARGINIQ ER tablet strengths available.
• Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to TARGINIQ ER.
• Titrate appropriately to a stable and tolerated dose.

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to TARGINIQ ER.

Conversion from Methadone to TARGINIQ ER
Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Conversion from Transdermal Fentanyl to TARGINIQ ER
Treatment with, TARGINIQ ER can be initiated after the transdermal fentanyl patch has been removed for at least 18 hours. Although there has been no systematic assessment of such conversion, start with a conservative conversion: substitute 10 mg/5 mg of TARGINIQ ER every 12 hours for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to TARGINIQ ER, as there is limited documented experience with this conversion.

Conversion from Transdermal Buprenorphine to TARGINIQ ER
For patients receiving transdermal buprenorphine (<20 mcg/hr), the recommended starting dose is TARGINIQ ER 10 mg/5 mg every 12 hours. Follow the patient closely during conversion from transdermal buprenorphine to TARGINIQ ER, as there is limited experience with this conversion.

2.3 Titration and Maintenance of Therapy

Individually titrate TARGINIQ ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving TARGINIQ 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, and 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 the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of TARGINIQ 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 TARGINIQ ER dose.

As a guideline, the dose of TARGINIQ ER can be up-titrated from the current dose by increasing the dose 10 mg/5 mg q12h every 1 to 2 days as needed based on efficacy, safety, and tolerability. The total daily dose of TARGINIQ ER should not exceed 80 mg/40 mg (40 mg/20 mg q12h).

The highest total daily dose of TARGINIQ ER studied in the main clinical program is 80 mg/40 mg (40 mg/20 mg twice daily). Total daily doses above 80 mg/40 mg have not been studied sufficiently to ensure patient safety and may be associated with symptoms of opioid withdrawal or decreased analgesia.

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 Dosage Modifications with Concomitant Use of Central Nervous System Depressants

If the patient is currently taking a central nervous system (CNS) depressant and the decision is made to begin TARGINIQ ER, start with one-third to one-half the recommended starting dosage of TARGINIQ ER, consider using a lower dosage of the concomitant CNS depressant, and monitor patients for signs of respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.4), Drug Interactions (7)].

2.5 Dosage Modifications in Patients with Mild Hepatic Impairment

TARGINIQ ER is contraindicated in patients with moderate and severe hepatic impairment. When administering TARGINIQ ER to patients with mild hepatic impairment, reduce the dose to one-third to one-half the usual starting dose followed by careful dose titration. Monitor for signs of respiratory depression, sedation, and hypotension [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.6 Dosage Modifications in Patients with Renal Impairment

When administering TARGINIQ ER to patients with renal impairment, reduce the initial dose to one-half the usual starting dose followed by careful dose titration. Monitor for signs of respiratory depression, sedation, and hypotension [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].

2.7 Discontinuation of TARGINIQ ER

When the patient no longer requires therapy with TARGINIQ 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 TARGINIQ ER [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

Table 3 presents a suggested taper schedule that was used in a clinical trial to discontinue patients from TARGINIQ ER:

5.1 Addiction, Abuse, and Misuse

TARGINIQ ER contains oxycodone, a Schedule II controlled substance. As an opioid, TARGINIQ ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as TARGINIQ 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 TARGINIQ ER. Addiction can occur at recommended doses and if the drug is misused or abused.

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

Abuse or misuse of TARGINIQ ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of oxycodone and can result in overdose and death [see Overdosage (10)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing TARGINIQ 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 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 TARGINIQ 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 and following dosage increases of TARGINIQ ER.

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

Accidental ingestion of even one dose of TARGINIQ 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 TARGINIQ 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 TARGINIQ ER with a CYP3A4 inhibitor, 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 TARGINIQ ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in TARGINIQ ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using TARGINIQ ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in TARGINIQ ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of TARGINIQ ER until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of TARGINIQ 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 TARGINIQ 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 from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression coma, and death may result from the concomitant use of TARGINIQ ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when TARGINIQ ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

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

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

Patients with Chronic Pulmonary Disease: TARGINIQ ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of TARGINIQ ER [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Monitor such patients closely, particularly when initiating and titrating TARGIIQ ER and when TARGINIQ ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.5)]. Alternatively, consider the use of non-opioid analgesics in these patients.

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

TARGINIQ 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 (7.1)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of TARGINIQ ER. In patients with circulatory shock, TARGINIQ ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of TARGINIQ 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), TARGINIQ 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 TARGINIQ ER.

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

5.10 Risks of Use in Patients with Gastrointestinal Conditions

TARGINIQ ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The oxycodone in TARGINIQ ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the 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 TARGINIQ ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during TARGINIQ 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 are receiving a full opioid agonist analgesic, including TARGINIQ ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing TARGINIQ ER, gradually taper the dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue TARGINIQ ER [see Drug Abuse and Dependence (9.3)].

Symptoms of opioid withdrawal occurred in some patients in clinical trials [see Adverse Reactions (6.1)]. Symptoms included but were not limited to hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Monitor patients for symptoms of opioid withdrawal. In opioid-tolerant patients, if symptoms of opioid withdrawal occur following conversion to TARGINIQ ER or following dose escalation, consider lowering the dose to determine whether symptoms are reduced.

Parenteral use of naloxone has been associated with abrupt and complete reversal of opioid effects leading to withdrawal symptoms (e.g., abdominal cramping, muscle aches, sweating, anxiety, nausea, vomiting, diarrhea). Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, and pulmonary edema have been associated with parenteral naloxone used postoperatively.

5.13 Risks of Driving and Operating Machinery

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

5.14 Laboratory Monitoring

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 Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2,396 patients were treated in controlled and open-label clinical studies with TARGINIQ ER. Seven hundred and ninety-four of these patients (33%) were treated for approximately six months and 621 (26%) were treated for approximately one year.

TARGINIQ ER may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)].

Commonly Observed Treatment-Emergent Adverse Reactions in a Clinical Study with TARGINIQ ER in Opioid-Experienced Patients with Uncontrolled Moderate to Severe Chronic Low Back Pain
The safety data described in Table 4 below are based on a 12-week, randomized, double-blind, placebo-controlled clinical trial in opioid-experienced patients with moderate to severe chronic low back pain. This trial included 1,095 TARGINIQ ER-treated patients in an open-label titration period, and 298 TARGINIQ ER-and 302 placebo-treated patients in a double-blind treatment period. The mean age was 52 years old; 55% were female, and 45% were male; 74% were Caucasian, 22% were Black, and 11% were Hispanic.

The most common treatment-emergent adverse reactions (reported by ≥ 5% of TARGINIQ ER subjects) during the open-label or double-blind periods were nausea and vomiting.

The most common reason for discontinuation during the open-label period due to treatment-emergent adverse reactions (reported by ≥ 1% of subjects) was nausea (2%).

The most common reason for discontinuation during the double-blind period due to treatment-emergent adverse reactions (reported by ≥ 1% of subjects with TARGINIQ ER or placebo) was drug withdrawal syndrome (<1% vs. 1%), respectively.

The incidence of treatment-emergent adverse reactions reported by ≥ 2% of subjects in a clinical trial comparing TARGINIQ ER with placebo is shown in Table 4 below:

In a clinical trial, the following adverse reactions were reported in patients treated with TARGINIQ ER with an incidence between ≥ 1% and <2%:

Eye disorders: lacrimation increased
General disorders and administration site conditions: fatigue
Infections and infestations: influenza
Injury, poisoning, and procedural complications: fall
Musculoskeletal and connective tissue disorders: arthralgia
Nervous system disorders: dizziness, sinus headache, somnolence
Psychiatric disorders: drug abuse
Skin and subcutaneous tissue disorders: pruritus, rash, cold sweat
Vascular disorders: hot flush, hypertension

6.2 Postmarketing Experience

The following most frequently reported adverse reactions have been identified during post-approval use of oxycodone/naloxone extended-release tablets. 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.

Gastrointestinal Disorders: abdominal pain, constipation, diarrhea, nausea, and vomiting

General Disorders and Administration Site Conditions: drug withdrawal syndrome, fatigue, pain, malaise, and drug ineffective

Injury, Poisoning, and Procedural Complications: inadequate analgesia

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): malignant neoplasm progression

Nervous System Disorders: dizziness, headache, tremor, and somnolence

Psychiatric Disorders: restlessness, confusional state, and anxiety

Respiratory, Thoracic, and Mediastinal Disorders: dyspnea

Skin and Subcutaneous Tissue Disorders: hyperhidrosis and pruritus

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 TARGINIQ ER.

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

8.1 Pregnancy

Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal [see Warnings and Precautions (5.3)]. There are no adequate and well-controlled studies with TARGINIQ ER in pregnant women. The naloxone component of TARGINIQ ER may precipitate opioid withdrawal in a fetus due to the immaturity of the fetal blood brain barrier. Animal reproduction studies were not conducted with the combination of oxycodone and naloxone, the components of TARGINIQ ER. However, animal data are available from studies conducted with the individual components. Embryo-fetal toxicity was not observed following oral administration of oxycodone to rats and rabbits during the period of organogenesis at doses equal to or 30 times, respectively, the maximum recommended daily dose (MRDD) of 80 mg oxycodone/day on a body surface area basis. Decreased pup weight was observed in rats with oral administration of oxycodone throughout pregnancy at doses 0.8 times the MRDD dose of 80 mg oxycodone/day. Embryo-fetal toxicity was not observed following oral administration of naloxone (800 mg/kg or 400 mg/kg) to pregnant rats and rabbits, respectively, during organogenesis at doses 192 times the MRDD of 40 mg naloxone/day, on a body surface area basis. In several published studies, treatment of pregnant rats with oxycodone hydrochloride 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 estimated 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.

Clinical Considerations
Fetal/neonatal adverse reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of narcotic-opioid induced respiratory depression in the neonate. TARGINIQ ER is not recommended for use in women during or immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including TARGINIQ ER, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data
There are no studies examining the reproductive and developmental effects of the combination of oxycodone and naloxone; however, there are data with the individual agents.

Oxycodone

Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/kg/day and rabbits up to 125 mg/kg/day, equivalent to 1 and 30 times the maximum total daily dose of 80 mg oxycodone/day, respectively on a mg/m2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no long-term developmental or reproductive effects in the pups.

Oxycodone hydrochloride was administered orally to female rats during gestation and lactation in a pre- and postnatal toxicity study. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by mothers given the highest dose used (6 mg/kg/day, equivalent to approximately 0.8-times the maximum total daily dose of 80 mg/day, on a mg/m2 basis). However, body weight of these pups recovered.

In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3 times an adult human oral dose of 60 mg/day on a mg/m2 basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/m2 basis).

Naloxone

Orally administered naloxone was not teratogenic in the rat or rabbit at the maximum dosages tested (800 mg/kg/day or 400 mg/kg/day, respectively) which were equivalent to approximately 192-times the intake of naloxone at the maximum recommended dose of 40 mg naloxone/day on a mg/m2 basis.

In a peri-/post-natal development study with naloxone in rats, the highest dosage of 800 mg/kg/day (192-times the intake of naloxone at the maximum total daily dose of 40 mg naloxone/day, on a mg/m2 basis) produced mortality and significant toxicity in maternal rats, which was associated with increased pup deaths in the immediate postpartum period. Mild toxic signs were also observed in maternal rats that received 200 mg/kg/day (approximately 48-times the intake of naloxone at the maximum daily dose of 40 mg naloxone on a body surface area basis); however, there were no adverse effects on the pups.

8.2 Lactation

Risk Summary

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 TARGINIQ ER. It is unknown whether naloxone is present in breast milk. Instruct patients not to undertake nursing while receiving TARGINIQ ER. 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 TARGINIQ ER.

Clinical Considerations
Infants exposed to TARGINIQ ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Furthermore, naloxone may precipitate opioid withdrawal in a breast-fed infant.

8.3 Females and Males of Reproductive Potential

Infertility

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)].

8.4 Pediatric Use

Safety and effectiveness of TARGINIQ ER in pediatric patients below the age of 18 years have not been established.

8.5 Geriatric Use

A prospective study conducted in two age groups (younger: 19-44 years old vs. elderly: 65-77 years old) to assess age effects on the PK of TARGINIQ ER (10 mg/5 mg) demonstrated slightly higher steady-state oxycodone AUC (18% increase), and higher steady-state naloxone AUC (82% increase) for elderly subjects compared with younger subjects. Evaluate elderly patients at frequent intervals and consider TARGINIQ ER dose adjustments until stable drug effects are achieved.

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 TARGINIQ ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)].

Oxycodone and naloxone are 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

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)].

9.1 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 ER
TARGINIQ 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.

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

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.

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

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.

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

Summary
Based 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)].

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.

TARGINIQ ER should not be abruptly discontinued [see Dosage and Administration (2.7)]. If TARGINIQ 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, 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)].

12.1 Mechanism of Action

Oxycodone
Oxycodone hydrochloride is a full opioid agonist and is relatively selective for the mu 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 to analgesia for 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.

Naloxone
Naloxone is an antagonist acting on mu, kappa, and delta opioid receptors in the brain, spinal cord, and peripheral organs (e.g, intestine, heart, kidney, and lungs). Naloxone antagonizes opioid effects by competing for the mu, kappa, and delta opioid receptor sites with the greatest affinity for the mu receptor. Naloxone produces opioid withdrawal signs and symptoms in individuals physically dependent on opioid agonists when administered parenterally.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in CO2 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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage (10)].

Naloxone prevents or reverses the effects of opioids, including respiratory depression and sedation, when administered intravenously [see Overdosage (10)]. When naloxone is administered orally, at the same doses as in TARGINIQ ER, these effects would not be expected due to low circulating plasma concentrations.

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, 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.

Concentration –Efficacy Relationships

Studies with oxycodone in normal volunteers and patients reveal predictable relationships between oxycodone dosage and plasma oxycodone concentrations, as well as between concentration and certain expected opioid effects, such as pupillary constriction, sedation, overall subjective “drug effect”, and analgesia.

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 (2.1, 2.3)].

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)].

12.3 Pharmacokinetics

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

Cutting, breaking, chewing, crushing, or dissolving TARGINIQ ER impairs the extended-release delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone.

Absorption

Oxycodone
Oxycodone from TARGINIQ ER tablets was rapidly absorbed with the median Tmax 3 to 4 hours following a single oral administration over a range of doses from 10 mg/5 mg to 80 mg/40 mg. About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a parenteral dose. This high oral bioavailability is due to low pre-systemic and/or first-pass metabolism. Dose proportionality for oxycodone has been established for the 10 mg/5 mg, 20 mg/10 mg, and 40 mg/20 mg TARGINIQ ER tablet strengths for both peak plasma concentrations (Cmax) and extent of absorption (AUC) (see Table 8 and Table 9, below) following single or multiple oral dose with q12h administration. Steady-state plasma concentrations are reached in approximately 2 days for oxycodone and naloxone and for their metabolites.

Naloxone
Absolute bioavailability of naloxone from TARGINIQ ER tablets was very low (≤ 2%) following oral administration. However in an abuse potential study conducted in nondependent drug users, naloxone bioavailability was much higher (approximately 31%) following intranasal administration of crushed TARGINIQ ER 40 mg/20 mg tablets, due to circumvention of GI and hepatic first-pass naloxone metabolism. Mean AUC and Cmax values of naloxone were 29.9 nghr/mL and 20.2 ng/mL following intranasal administration of crushed TARGINIQ ER 40 mg/20 mg tablets, while mean AUC and Cmax values were 0.833 ng hr/mL and 0.0845 ng/mL under normal use condition [see Drug Abuse and Dependence (9.2)].

Food Effect:

Administration of TARGINIQ ER with a standardized high-fat meal did not meaningfully affect the extent of absorption of oxycodone, naloxone, or naloxone-3β-glucuronide. In the clinical trial program, TARGINIQ ER was administered to chronic pain patients without regard to meals. Therefore, TARGINIQ ER can be administered with or without food.

Distribution

Oxycodone
Plasma protein binding for oxycodone measured in healthy subjects was <24%. Following IV administration, the mean volume of distribution for oxycodone (0.07 mg/kg) was 245 L. Once absorbed, oxycodone is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone is found in breast milk [see Use in Specific Populations (8.3)]. Oxycodone crossed the blood-brain barrier in preclinical species.

Naloxone
Plasma protein binding for naloxone measured in healthy subjects, was <60%. Following IV administration, the mean volume of distribution for naloxone (0.035 mg/kg) was 378 L. It is not known whether naloxone passes into breast milk. Naloxone crossed the blood-brain barrier in preclinical species.

Elimination

Metabolism

Oxycodone:
Oxycodone metabolism is primarily mediated by CYP3A4/5 and CYP2D6. Oxycodone is mainly metabolized to Phase 1 metabolites including noroxycodone, oxymorphone and noroxymorphone. Oxycodone metabolites are present in plasma at lower concentrations than the parent drug. Noroxycodone and noroxymorphone are the major metabolites in the blood circulation. The mean molar ratio of metabolite to parent (oxycodone), as evaluated by AUC across proposed therapeutic doses of TARGINIQ ER, was 0.928 for noroxycodone, 0.379 for noroxymorphone, and 0.0251 for oxymorphone, respectively.

Naloxone:
Naloxone metabolism is primarily mediated by UGT1A8 and UGT2B7. Naloxone is mainly metabolized to 6β-naloxol, naloxone-3β-glucuronide and 6β-naloxol-3β-glucuronide. The mean molar ratio of metabolite to parent (naloxone), as evaluated by AUC across proposed therapeutic doses TARGINIQ ER was 31.5 for 6β-naloxol, 1459 for naloxone-3β-glucuronide, and 1301 for 6β-naloxol-3β-glucuronide, respectively. Naloxone metabolites were present in plasma at higher concentrations than the parent drug, especially for naloxone-3β-glucuronide and 6β-naloxol-3β-glucuronide due to the extremely low plasma naloxone concentrations following oral administration of TARGINIQ ER.

Excretion

Oxycodone:
Oxycodone is rapidly eliminated from the body with a mean t1/2 of approximately 3.9-5.3 hours after a single oral dose administration of TARGINIQ ER in healthy subjects. Oxycodone and its metabolites are excreted in both urine and feces. Following an IV dose (0.07 mg/kg), the mean total plasma clearance was 47.8 L/hour in healthy subjects. Following TARGINIQ ER 10/5 mg administration, the mean renal clearance was approximately 3.66-4.37 L/hour. Following an oral dose of oxycodone immediate-release (15 mg), the mean total urine recovery (48 hour cumulative recovery) of oxycodone and its metabolites from 16 healthy subjects was 72%. These findings suggest that metabolism is the major route of elimination.

Naloxone:
Naloxone is eliminated from the body with mean t1/2 ranging from 4.1 to 17.2 hours after a single oral dose administration of TARGINIQ ER in healthy subjects. The mean total plasma clearance was 217 L/hour following an IV dose (0.035 mg/kg), and the mean renal clearance was 7.85-31.9 L/hour following an oral dose of TARGINIQ ER 10 mg/5 mg. These findings suggest that the metabolism is the major route of elimination.

Special Populations

Age: Geriatric Population

A prospective study conducted in 2 age groups (younger: 19-44 years old vs. elderly: 65-77 years old) to assess age effects on the PK of TARGINIQ ER (10 mg/5 mg) demonstrated slightly higher steady state oxycodone AUC (18% increase), and higher steady state naloxone AUC (82% increase) for elderly subjects compared with younger subjects. [see Use in Specific Populations (8.6)]

Sex

Pharmacokinetic properties of TARGINIQ ER were not affected by sex.

Hepatic Impairment

Oxycodone:
Oxycodone pharmacokinetics from TARGINIQ ER was significantly altered by hepatic impairment, especially in subjects with moderate or severe hepatic impairment as compared with healthy subjects. Mean oxycodone AUC was 99.1, 143, 319 and 314 nghr/mL for healthy subjects, and subjects with mild, moderate, and severe hepatic impairment, respectively. The mean increase in oxycodone AUC was approximately 43%, 219%, and 210% for subjects with mild, moderate, and severe hepatic impairment, respectively, as compared with that for healthy subjects. Mean oxycodone Cmax was 9.00, 10.8, 18.1 and 17.2 ng/mL for healthy subjects, and subjects with mild, moderate, and severe hepatic impairment, respectively. The mean increase in oxycodone Cmax was approximately 20%, 101%, and 91% for subjects with mild, moderate, and severe hepatic impairment, respectively, as compared with that for healthy subjects.

Naloxone:
Following oral TARGINIQ ER administration, mean naloxone AUC0-t was 0.115, 1.02, 0.459 and 1.12 ng•hr/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. Mean naloxone Cmax was 0.0345, 0.0435, 0.0347 and 0.0678 ng/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in naloxone Cmax was approximately 976%, 758%, and 1575% for subjects with mild, moderate, and severe renal impairment, respectively, as compared with that for healthy subjects [see Use in Specific Populations (8.7)].

Renal Impairment

Oxycodone:
Following oral TARGINIQ ER administration, mean oxycodone AUC was 111, 171, 186 and 253 nghr/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in oxycodone AUC was approximately 53%, 66% and 124% for subjects with mild, moderate and severe renal impairment, respectively, as compared with that for healthy subjects. Mean oxycodone Cmax was 10.6, 11.7, 14.4 and 17.8 ng/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in oxycodone Cmax was approximately 10%, 35%, and 67% for subjects with mild, moderate, and severe renal impairment, respectively, as compared with that for healthy subjects. [see Use in Specific Populations (8.8)]

Naloxone:
Following oral TARGINIQ ER administration, mean naloxone AUC0-t was 0.115, 1.02, 0.459 and 1.12 nghr/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. Mean naloxone Cmax was 0.0345, 0.0435, 0.0347 and 0.0678 ng/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in naloxone Cmax was approximately 976%, 758%, and 1575% for subjects with mild, moderate, and severe renal impairment, respectively, as compared with that for healthy subjects [see Use in Specific Populations (8.8)].

Drug Interaction Studies

Oxycodone
At therapeutic concentrations, TARGINIQ ER is not expected to affect concomitantly administered medicines metabolized by CYP1A2, CYP2A6, CYP2C9/19, CYP2D6, CYP2E1 and CYP3A4. There were no pharmacokinetic drug interactions between oxycodone and naloxone.

CYP3A4 Inhibitors:
CYP3A4 is the major enzyme involved in noroxycodone formation. Co-administration of an oxycodone controlled release tablet (10 mg single dose) and the CYP3A4 inhibitor ketoconazole (200 mg BID) increased oxycodone AUC and Cmax by 170% and 100%, respectively [see Drug Interactions (7)].

CYP3A4 Inducers:
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 Drug Interactions (7)].

CYP2D6 Inhibitors:
Oxycodone is metabolized in part to oxymorphone via CYP2D6. While this pathway may be blocked by a variety of drugs such as certain cardiovascular drugs (e.g., quinidine) and antidepressants (e.g., fluoxetine), such blockade has not been shown to be of clinical significance with TARGINIQ ER [see Drug Interactions (7)].

Naloxone
UGT1A8 and 2B7 are responsible for the metabolism of naloxone. Metabolic drug interactions with naloxone are unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenicity studies have not been conducted with oxycodone alone or the oxycodone and naloxone combination.

Naloxone was tested in two carcinogenicity studies in rats and transgenic mice. Naloxone was not carcinogenic in a 2-year rat bioassay at doses as high as 100 mg/kg/day (24-times the maximum recommended daily dose of 40 mg naloxone/day on a mg/m2 basis).

Naloxone did not produce evidence of carcinogenic potential in the Tg.rasH2 mouse model.

Mutagenesis
Oxycodone was genotoxic in the mouse lymphoma assay. Clastogenicity was observed with oxycodone in the presence of metabolic activation in one chromosomal aberration assay in human lymphocytes at concentrations greater than or equal to 1250 mcg/mL at 24 but not 48 hours of exposure. In a second chromosomal aberration assay with human lymphocytes, no structural clastogenicity was observed either with or without metabolic activation; however, in the absence of metabolic activation, oxycodone increased numerical chromosomal aberrations (polyploidy). Oxycodone was not genotoxic in the following assays: Ames S. typhimurium and E. coli test with and without metabolic activation at concentrations up to 5000 µg/plate, chromosomal aberration test in human lymphocytes (in the absence of metabolic activation) at concentrations up to 1500 µg/mL, and with activation after 48 hours of exposure at concentrations up to 5000 µg/mL, and in the in vivo bone marrow micronucleus assay in mice (at plasma levels up to 48 µg/mL).

Naloxone was genotoxic in the mouse lymphoma assay. Naloxone produced a non-dose-related increase in chromosomal aberrations in the presence of metabolic activation that was statistically significant at concentrations of 375 and 1500 mcg/mL but not at 750 or 3000 mcg/mL. In contrast, naloxone was not mutagenic in the S. typhimurium/E. coli bacterial mutagenicity test with or without metabolic activation nor was it genotoxic in in vivo mouse bone marrow micronucleus test at a dose of 500 mg/kg.

Impairment of Fertility
Fertility studies to evaluate the combination of oxycodone and naloxone have not been conducted. In a study of reproductive performance, rats were administered a once daily gavage dose of the vehicle or oxycodone hydrochloride doses up to 8 mg/kg (equivalent to the maximum recommended daily dose of 80 mg/day on a mg/m2 basis). Male rats were dosed for 28 days before cohabitation with females, during the cohabitation and until necropsy (2-3 weeks post-cohabitation). Females were dosed for 14 days before cohabitation with males, during cohabitation and up to Gestation Day 6. Oxycodone hydrochloride did not affect reproductive function in male or female rats.

Oral administration of naloxone to male and female rats at dosages as high as 800 mg/kg/day had no effect on fertility or general reproductive performance (approximately 192-times the maximum recommended daily dose of 40 mg naloxone/day, on a mg/m2 basis).