Xtampza ER

What Is Xtampza ER?

Xtampza ER (oxycodone) extended-release is an opioid agonist product 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.

What Are Side Effects of Xtampza ER?

Common side effects of Xtampza ER include:

• nausea
• headache
• constipation
• drowsiness
• itching
• vomiting
• dizziness
• blurred vision
• abdominal pain
• diarrhea
• gastroesophageal reflux disease (GERD)
• chills
• fatigue
• irritability
• fever
• swelling
• loss of appetite
• joint, back, or muscle pain
• migraine
• tremor
• anxiety
• insomnia
• cough
• mouth and throat pain
• increased sweating
• rash
• hot flashes
• high blood pressure

Dosage for Xtampza ER

The initial dose of Xtampza ER is 9 mg (equivalent to 10 mg oxycodone HCl) capsules orally every 12 hours with food. The daily dose of Xtampza ER must be limited to a maximum of 288 mg per day (equivalent to 320 mg oxycodone HCl per day).

What Drugs, Substances, or Supplements Interact with Xtampza ER?

Xtampza ER may interact with macrolide antibiotics, azole antifungals, protease inhibitors, rifampin, carbamazepine, phenytoin, alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, mirtazapine, trazodone, tramadol, monoamine oxidase (MAO) inhibitors, diuretics, and anticholinergics. Tell your doctor all medications and supplements you use.

Xtampza ER During Pregnancy and Breastfeeding

Xtampza ER is not recommended for us during pregnancy; it may harm a fetus. Xtampza ER passes into breast milk and may cause undesirable side effects in a nursing infant. Xtampza ER is not recommended for use while breastfeeding. Withdrawal symptoms may occur if you suddenly stop taking Xtampza ER.

Additional Information

Our Xtampza ER (oxycodone) extended-release Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

 

Xtampza ER Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Opioid medicine can slow or stop your breathing, and death may occur. A person caring for you should give naloxone and/or seek emergency medical attention if you have slow breathing with long pauses, blue colored lips, or if you are hard to wake up.

Call your doctor at once if you have:

• noisy breathing, sighing, shallow breathing, breathing that stops during sleep;
• a slow heart rate or weak pulse;
• a light-headed feeling, like you might pass out;
• confusion, unusual thoughts or behavior;
• seizure (convulsions);
• low cortisol levels-- nausea, vomiting, loss of appetite, dizziness, worsening tiredness or weakness; or
• high levels of serotonin in the body--agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea.

Serious breathing problems may be more likely in older adults and in those who are debilitated or have wasting syndrome or chronic breathing disorders.

Common side effects may include:

• drowsiness, headache, dizziness, tiredness; or
• constipation, stomach pain, nausea, vomiting.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Xtampza ER (Oxycodone Extended-release Capsules)

 

Xtampza ER Professional Information

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
• Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
• Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
• Interactions with Benzodiazepines or Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
• Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
• Severe Hypotension [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Withdrawal [see WARNINGS AND PRECAUTIONS]

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.

The safety of XTAMPZA ER was evaluated in a Phase 3, randomized-withdrawal, double-blind clinical trial involving 740 patients with moderate-to-severe chronic lower back pain. In the double-blind maintenance phase, 389 patients were randomized and 193 patients were assigned to the XTAMPZA ER treatment group.

The most common AEs (>5%) reported by patients in the Phase 3 clinical trial during the titration phase were: nausea (16.6%), headache (13.9%), constipation (13.0%), somnolence (8.8%), pruritus (7.4%), vomiting (6.4%), and dizziness (5.7%).

The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing XTAMPZA ER with placebo are shown in Table 1 below:

Table 1: Common Adverse Reactions (>5%)

Adverse Reaction	Titration	Maintenance
	XTAMPZA ER (n = 740) (%)	XTAMPZA ER (n = 193) (%)	Placebo (n = 196)(%)
Nausea	16.6	10.9	4.6
Headache	13.9	6.2	11.7
Constipation	13.0	5.2	0.5
Somnolence	8.8	<1	<1
Pruritus	7.4	2.6	1.5
Vomiting	6.4	4.1	1.5
Dizziness	5.7	1.6	0

In the Phase 3 clinical trial, the following adverse reactions were reported in patients treated with XTAMPZA ER with incidences of 1% to 5%:

Eye disorders: vision blurred

Gastrointestinal disorders: abdominal pain, upper abdominal pain, diarrhea, gastroesophageal reflux disease

General disorders and administration site conditions: chills, drug withdrawal syndrome, fatigue, irritability, edema, pyrexia

Injury, poisoning and procedural complications: excoriation

Metabolism and nutrition disorders: decreased appetite, hyperglycemia

Musculoskeletal and connective tissue disorders: arthralgia, back pain, musculoskeletal pain, myalgia

Nervous system disorders: migraine, tremor

Psychiatric disorders: anxiety, insomnia, withdrawal syndrome

Respiratory, thoracic and mediastinal disorders: cough, oropharyngeal pain

Skin and subcutaneous tissue disorders: hyperhidrosis, rash

Vascular disorders: hot flush, hypertension

In the Phase 3 clinical trial, the following treatment-related adverse reactions were reported in patients treated with XTAMPZA ER with incidences of less than 1% of patients.

Investigations: increased gamma-glutamyl transferase, increased heart rate

Nervous system disorders: lethargy, memory impairment, poor-quality sleep

Psychiatric disorders: abnormal dreams, euphoric mood, restlessness

Respiratory, thoracic and mediastinal disorders: dyspnea

Skin and subcutaneous tissue disorders: night sweats

Postmarketing Experience

The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin Syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis

Anaphylaxis has been reported with ingredients contained in XTAMPZA ER.

Androgen Deficiency

Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].

DRUG INTERACTIONS

Table 2 includes clinically significant drug interactions with XTAMPZA ER.

Table 2: Clinically Significant Drug Interactions with XTAMPZA ER

Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of XTAMPZA ER and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of XTAMPZA ER and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of XTAMPZA ER is achieved [see WARNINGS AND PRECAUTIONS]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of XTAMPZA ER until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of XTAMPZA ER and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see WARNINGS AND PRECAUTIONS]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved [see DOSAGE AND ADMINISTRATION]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider XTAMPZA ER dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacological effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Examples	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue XTAMPZA ER if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)].
Intervention:	The use of XTAMPZA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of XTAMPZA ER and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of XTAMPZA ER and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when XTAMPZA ER is used concomitantly with anticholinergic drugs.

Drug Abuse And Dependence

Controlled Substance

XTAMPZA ER contains oxycodone, a Schedule II controlled substance.

Abuse

XTAMPZA ER contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].

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 addicts. In addition, abuse of opioids can occur in the absence of true addiction.

XTAMPZA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping 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 XTAMPZA ER

XTAMPZA ER is for oral use only. Abuse of XTAMPZA ER poses a risk of overdose and death. The risk is increased with concurrent use of XTAMPZA ER with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Abuse Deterrence Studies

XTAMPZA ER capsules contain microspheres formulated with inactive ingredients intended to make the formulation more difficult to manipulate for misuse and abuse.

In Vitro Testing

In vitro physical and chemical manipulation studies were performed to evaluate the success of different methods of defeating the extended-release formulation.

Results support that, relative to immediate-release oxycodone tablets, XTAMPZA ER is less susceptible to the effects of grinding, crushing, and extraction using a variety of tools and solvents.

XTAMPZA ER resisted attempts to pass the melted capsule contents or the microspheres suspended in water through a hypodermic needle.

Pharmacokinetic Studies

The pharmacokinetic profile of manipulated XTAMPZA ER capsule contents (36 mg; [equivalent to 40 mg oxycodone HCl]) was characterized following oral (three studies) and intranasal (two studies) administration. The studies were conducted in a randomized, cross-over design. In studies assessing manipulation by crushing, the most effective crushing method identified in previous in vitro studies was applied to the product(s).

Oral Pharmacokinetic Studies, Manipulated And Intact XTAMPZA ER

The effect of two types of product manipulation (crushing and chewing) on XTAMPZA ER pharmacokinetics was measured in three studies.

In one oral pharmacokinetic study, XTAMPZA ER capsule contents were crushed or chewed prior to oral administration in healthy, naltrexone-blocked volunteers. The two comparators in this study were intact XTAMPZA ER capsules and an immediate-release solution of oxycodone at an equivalent dose.

In two oral pharmacokinetic studies, XTAMPZA ER capsule contents were crushed prior to oral administration in healthy, naltrexone-blocked volunteers. The comparators in these studies included intact XTAMPZA ER capsules, intact and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets at an equivalent dose, and crushed immediate-release oxycodone tablets at an equivalent dose.

The data displayed in Table 3 illustrate the findings from the oral pharmacokinetic studies (data were similar for the two oral pharmacokinetic studies comparing XTAMPZA ER to OXYCONTIN). Collectively, the data demonstrated that crushing or chewing XTAMPZA ER prior to administration did not increase the maximum observed plasma concentration (Cmax) or total exposure (AUC0-INF) relative to dosing the intact product under fed conditions. Relative to immediate-release oxycodone and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets, the Cmax for all XTAMPZA ER treatments was lower and the Tmax longer, consistent with an extended-release profile.

Table 3: Oxycodone Pharmacokinetic Parameters, Administration of Manipulated and Intact Dosage Forms (36mg of XTAMPZA ER or equivalent)

Treatment	Cmax (ng/mL)	Tmax (hr)	AUC0-INF (hr•ng/mL)
	Oral Pharmacokinetic Study 1
Intact XTAMPZA ER Capsules (fed)	62.3 (13.0)	4.0 (1.5-6)	561(124)
Crushed XTAMPZA ER Capsule Contents (fed)	57.6 (12.6)	4.5 (2.5-6)	553(134)
Chewed XTAMPZA ER Capsule Contents (fed)	55.6 (10.9)	4.5 (2.5-8)	559 (113)
Immediate-Release Oxycodone Solution (fasted)	115 (27.3)	0.75 (0.5-2)	489 (80.2)
	Oral Pharmacokinetic Study 2
Intact XTAMPZA ER Capsules (fed)	67.5 (17.6)	3.5 (1.25 - 6.0)	581 (138)
Crushed XTAMPZA ER Capsule Contents (fed)	62.9 (12.6)	4.0 (2.0 - 7.0)	597(149)
Intact reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed)	64.9 (13.8)	5.0 (2.0-10.0)	611(145)
Crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed)	78.4 (12.9)	1.75 (0.5-5.0)	587(132)
Crushed Immediate-Release Oxycodone Tablets (fed)	79.4 (17.1)	1.75 (0.5-4.0)	561(146)
Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum).

Nasal Pharmacokinetic Studies

The pharmacokinetic profile following intranasal administration of crushed XTAMPZA ER capsule contents was characterized in two clinical studies.

In Nasal Pharmacokinetic Study 1, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent, naltrexone-blocked subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and oxycodone HCl powder (intranasal) at an equivalent dose.

In Nasal Pharmacokinetic Study 2, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and crushed oxycodone immediate-release tablets (intranasal) at an equivalent dose.

The results of Nasal Pharmacokinetic Studies 1 and 2 are comparable and both studies demonstrated that intranasal administration of crushed XTAMPZA ER capsule contents did not result in higher peak plasma concentration (Cmax) or shorter time to peak concentration (Tmax) than taking XTAMPZA ER orally. The data from Nasal Pharmacokinetic Study 2 are displayed in Table 4 to represent these findings.

Table 4: Oxycodone Pharmacokinetic Parameters, Nasal Pharmacokinetic Study 2

Treatment	Cmax (ng/mL)	Tmax (hr)	AUC0-INF (hr•ng/mL)
Intact XTAMPZA ER Capsules (oral)	41.0 (10.0)	5.1 (1.6-8.1)	477 (89.6)
Crushed XTAMPZA ER Capsule Contents (nasal)	29.8 (6.6)	5.1 (1.6-12.1)	459 (106)
Crushed Immediate-Release Tablets (nasal)	60.9 (11.9)	2.6 (0.3-6.1)	577(124)
Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum).

Clinical Studies

Oral Abuse Potential Studies

The oral abuse potential of chewed XTAMPZA ER was evaluated in two studies.

In a randomized, double-blind, active- and placebo-controlled, single-dose, six-way crossover pharmacodynamic study, 52 non-dependent recreational opioid users received orally-administered active and placebo treatment. The six treatment arms were intact XTAMPZA ER (36 mg, fed and fasted); chewed XTAMPZA ER (36 mg, fed and fasted); crushed immediate-release (IR) oxycodone HCl in solution (40 mg, fasted, equivalent to 36 mg of XTAMPZA ER), and placebo. Data for chewed and intact XTAMPZA ER and crushed IR oxycodone in the fasted state are described below.

Drug Liking was measured on a bipolar 100-point Visual Analog Scale (VAS) where 50 represents a neutral response, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar 100-point VAS where 50 represents a neutral response, 0 represents the strongest negative response (e.g., ‘definitely would not take drug again'), and 100 represents the strongest positive response (e.g., ‘definitely would take drug again').

Fifty-two subjects completed the study, and the results are summarized in Table 5. The oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking and Take Drug Again VAS scores compared with crushed immediate-release oxycodone. In addition, the Drug Liking and Take Drug Again scores were similar for XTAMPZA ER taken in the intact and chewed states.

Table 5: Summary of Maximum Drug Liking and Take Drug Again (Emax) Following Oral Administration

		XTAMPZA ER Intact (Fasted)	XTAMPZA ER Chewed (Fasted)	Crushed IR Oxycodone (Fasted)	Placebo
Drug Liking*	Mean (SD)	73.9 (15.10)	73.3 (14.93)	86.40 (12.01)	55.8 (9.94)
(Emax)	Median (Range)	73.5 (50-100)	73.5 (50-100)	88.5 (52-100)	50.0 (50-86)
Take Drug Again	Mean (SD)	77.98 (21.07)	77.85 (18.30)	87.69 (12.90)	50.79 (21.41)
(Emax)*	Median (Range)	80.5 (1-100)	81.5 (50-100)	90.5 (50-100)	50.0 (0-100)
* Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation.

A prior, similarly-designed study was also conducted to evaluate the oral abuse potential of chewed XTAMPZA ER. Although the oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking scores compared with crushed immediate-release oxycodone, the results for Take Drug Again showed small differences that were not statistically significant.

Nasal Abuse Potential Study

In a randomized, double-blind, active- and placebo-controlled, single-dose, four-way crossover pharmacodynamic study, 39 recreational opioid users with a history of intranasal drug abuse received nasally administered active and placebo drug treatment. The four treatment arms were crushed XTAMPZA ER 36 mg dosed intranasally; intact XTAMPZA ER 36 mg dosed orally; crushed immediate-release oxycodone HCl 40 mg (equivalent to 36 mg of XTAMPZA ER) dosed intranasally; and placebo. Data for intranasal XTAMPZA ER and crushed immediate-release oxycodone are described below.

Thirty-six subjects completed the study. Intranasal administration of crushed XTAMPZA ER was associated with statistically lower mean Drug Liking and Take Drug Again scores compared with crushed immediate-release oxycodone (summarized in Table 6).

Table 6: Summary of Maximum Drug Liking and Take Drug Again (Emax) Following Intranasal Administration

		XTAMPZA ER Intranasal	Crushed IR Oxycodone Intranasal	Placebo
Drug Liking* (Emax)	Mean (SD)	61.81 (15.64)	82.72 (10.95)	54.5 (11.77)
	Median (Range)	59.5 (16-94)	84 (60-100)	51 (28-93)
Take Drug Again* (Emax)	Mean (SD)	47.67 (27.84)	71.36 (23.49)	45.92 (17.50)
	Median (Range)	50 (0-100)	78.5 (18-100)	50 (0-97)
* Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response). Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation.

Figure 1 demonstrates a comparison of Drug Liking for intranasal administration of crushed XTAMPZA ER compared to crushed immediate-release oxycodone in subjects who received both treatments (N=36). The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for XTAMPZA ER vs. immediate-release oxycodone greater than or equal to the value on the X-axis. Approximately 92% (n = 33) of subjects had some reduction in drug liking with XTAMPZA ER relative to crushed immediate-release oxycodone HCl. Approximately 78% (n = 28) of subjects had a reduction of at least 30% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl, and approximately 58% (n = 21) of subjects had a reduction of at least 50% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl.

Figure 1: Percent Reduction Profiles for Emax of Drug Liking VAS for Crushed XTAMPZA ER vs. Crushed Immediate-release Oxycodone, N=36 Following Intranasal Administration

Summary

The in vitro data demonstrate that XTAMPZA ER has physicochemical properties expected to make abuse by injection difficult. The data from pharmacokinetic and human abuse potential studies, along with support from the in vitro data, also indicate that XTAMPZA ER has physicochemical properties that are expected to reduce abuse via the oral and intranasal routes. The data from the oral pharmacokinetic studies of crushed or chewed XTAMPZA ER demonstrated a lack of dose dumping with no increase in oxycodone levels compared to intact XTAMPZA ER.

However, abuse of XTAMPZA ER by injection and by the oral and nasal routes of administration is still possible.

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

XTAMPZA 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. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS and Drug Abuse And Dependence].

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 is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting 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.

Do not abruptly discontinue XTAMPZA ER in a patient physically dependent on opioids. Rapid tapering of XTAMPZA ER in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing XTAMPZA ER, gradually taper the dosage using a patient- specific plan that considers the following: the dose of XTAMPZA ER the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use In Specific Populations].

Read the entire FDA prescribing information for Xtampza ER (Oxycodone Extended-release Capsules)