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Xtampza Er

(Oxycodone)

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Dosage & Administration

* XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

* XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

[see Warnings and Precautions (5.1)]

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments

[see Warnings and Precautions (5.2)].

XTAMPZA ER is administered, twice daily, every 12 hours, and

must be taken with food.

Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved

[see Clinical Pharmacology (12.3)]

* Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube

[see Dosage and Administration (2.7)].

* The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
* XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)
* XTAMPZA ER at a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone hydrochloride [HCl]) or a single dose greater than 36 mg (equivalent to 40 mg oxycodone HCl) is only for use in patients in whom tolerance to an opioid of comparable potency has been established. (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

XTAMPZA ER is administered, twice daily, every 12 hours, and

must be taken with food.

Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved

[see Clinical Pharmacology (12.3)]

[see Dosage and Administration (2.7)].

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)
* Patients considered 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 HCl 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. (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

XTAMPZA ER is administered, twice daily, every 12 hours, and

must be taken with food.

Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved

[see Clinical Pharmacology (12.3)]

[see Dosage and Administration (2.7)].

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)
* Use the lowest effective dose for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (

2 DOSAGE AND ADMINISTRATION

* XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
* XTAMPZA ER at a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone hydrochloride [HCl]) or a single dose greater than 36 mg (equivalent to 40 mg oxycodone HCl) is only for use in patients in whom tolerance to an opioid of comparable potency has been established.
* Patients considered 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 HCl 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 dose for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
* Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse .
* Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
* Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Consider prescribing naloxone based on the patient's risk factors for overdose.
* For opioid-naïve and opioid non-tolerant patients, initiate with 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).
*

Hepatic impairment

: Initiate therapy at 1/3 to 1/2 the usual dosage and titrate carefully. Regularly evaluate. Use alternate analgesia for patients requiring less than 9 mg.
* Do not abruptly discontinue XTAMPZA ER in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.
* Instruct patients to take XTAMPZA ER capsules with food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, XTAMPZA ER can also be taken by sprinkling the capsule contents on soft foods or into a cup and then administering directly into the mouth, or through a gastrostomy or nasogastric feeding tube.

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

XTAMPZA ER is administered, twice daily, every 12 hours, and

must be taken with food.

Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved

[see Clinical Pharmacology (12.3)]

[see Dosage and Administration (2.7)].

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

[see Warnings and Precautions (5.2)]

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

[see Warnings and Precautions (5.1, 5.2, 5.3)]

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

2.3 Initial Dosing

Use of XTAMPZA ER as the First Opioid Analgesic (Opioid-Naïve Patients)

Initiate treatment with XTAMPZA ER with one 9 mg capsule orally every 12 hours with food.

Use of XTAMPZA ER in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is XTAMPZA ER 9 mg orally every 12 hours with food.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from other Oral Oxycodone Formulations to XTAMPZA ER

Patients receiving other oral oxycodone formulations may be converted to XTAMPZA ER, using the same total daily dose of oxycodone, by administering one-half of the patient's total daily oral oxycodone dose as XTAMPZA ER every 12 hours with food. Because XTAMPZA ER is not bioequivalent to other oxycodone extended-release products, monitor patients for possible dosage adjustment

[see Dosage and Administration (2.1)].

Conversion from other Opioids to XTAMPZA ER

When XTAMPZA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There are no established conversion ratios for conversion from other opioids to XTAMPZA ER defined by clinical trials. Initiate dosing using XTAMPZA ER 9 mg orally every 12 hours with food.

It is safer to underestimate a patient's 24-hour oral oxycodone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxycodone dosage and manage adverse reactions due to an overdose. While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products.

Conversion from Methadone to XTAMPZA ER

Frequent evaluation 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 XTAMPZA ER

Eighteen hours following the removal of the transdermal fentanyl patch, XTAMPZA ER treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative oxycodone dose, approximately 9 mg (equivalent to 10 mg oxycodone HCl) every 12 hours of XTAMPZA ER, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to XTAMPZA ER, as there is limited documented experience with this conversion.

2.4 Dosage Modifications in Patients with Hepatic Impairment

For patients with hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration. Regularly evaluate for adverse events such as respiratory depression. Use of alternate analgesics is recommended for patients who require an XTAMPZA ER dose of less than 9 mg

[see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)]

2.5 Titration and Maintenance of Therapy

Individually titrate XTAMPZA ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving XTAMPZA ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as to reassess for the development of addiction, abuse, and misuse. 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 use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dose increase of XTAMPZA 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 XTAMPZA ER dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage

[see Warnings and Precautions (5)]

. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Because steady-state plasma concentrations are approximated in 1 to 2 days, XTAMPZA ER dosage may be adjusted every 1 to 2 days. If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dose 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. As a guideline, the total daily oxycodone dose usually can be increased by 25% to 50% of the current dose, each time an increase is clinically indicated.

2.6 Safe Reduction or Discontinuation of XTAMPZA ER

Do not abruptly discontinue XTAMPZA ER in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in 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. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking XTAMPZA ER, there are a variety of factors that should be considered, including the total daily dose of opioid (including XTAMPZA ER) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on XTAMPZA ER who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic

[see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)]

2.7 Administration of XTAMPZA ER

Instruct patients to always take XTAMPZA ER capsules with food and with approximately the same amount of food in order to ensure consistent plasma levels are achieved

[see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]

For patients who have difficulty swallowing, XTAMPZA ER can also be taken by sprinkling the capsule contents on soft foods or sprinkling the contents into a cup and then administering directly into the mouth or through a gastrostomy or nasogastric feeding tube. Patients who are unable to swallow a capsule should be instructed to:

* Open the capsule.
* Sprinkle the capsule contents (microspheres) onto a small amount of soft food (e.g., applesauce, pudding, yogurt, ice cream, or jam) or into a cup and then administer directly into the mouth and swallow immediately.
* Rinse the mouth to ensure all capsule contents (microspheres) have been swallowed.
* Discard the XTAMPZA ER capsule shells after the contents have been sprinkled on soft food or into a cup and then administered directly into the mouth.

The contents of the XTAMPZA ER capsules (microspheres) may be administered through a nasogastric tube or gastrostomy tube. When administering XTAMPZA ER through a nasogastric or gastrostomy tube:

* Flush the tube with water.
* Open an XTAMPZA ER capsule and carefully pour the microspheres directly into the tube. Do not pre-mix the capsule contents with the liquid that you will be using to flush them through the tube.
* Draw up 15 mL of water into a syringe, insert the syringe into the tube, and flush the microspheres through the tube.
* Repeat the flushing two more times, each with 10 mL of water, to ensure no microspheres remain in the tube.

Alternatively, milk or liquid nutritional supplement may be used as vehicles for flush and administration through feeding tubes.

5 WARNINGS AND PRECAUTIONS

Opioid-Induced Hyperalgesia and Allodynia

: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation.
*

Risk of life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients

: Regularly evaluate.
*

Adrenal Insufficiency

: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
*

Severe hypotension

: Regularly evaluate. Avoid use of XTAMPZA ER in patients with circulatory shock.
*

Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness

: Monitor for sedation and respiratory depression. Avoid use of XTAMPZA ER in patients with impaired consciousness or coma.

5.1 Addiction, Abuse, and Misuse

XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse

[see Drug Abuse and Dependence (9)]

. Because extended-release products such as XTAMPZA 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 XTAMPZA ER. Addiction can occur at recommended dosages and if the drug is misused or abused.

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

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death

[see Overdosage (10)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing XTAMPZA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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 XTAMPZA ER, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential

[see Dosage and Administration (2)]

. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

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

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see

Dosage and Administration (2.6)

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [

see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of XTAMPZA ER with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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 depressants 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]

Advise both patients and caregivers about the risks of respiratory depression and sedation when XTAMPZA 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)

5.4 Neonatal Opioid Withdrawal Syndrome

Use of XTAMPZA ER for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

[see Use in Specific Populations (8.1)]

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

* Complete a

REMS-compliant education program

offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
* Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
* Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
* Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

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

Concomitant use of XTAMPZA 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 XTAMPZA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in XTAMPZA ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using XTAMPZA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in XTAMPZA ER-treated patients, evaluate patients at frequent intervals and consider dosage reduction of XTAMPZA ER until stable drug effects are achieved

[see Drug Interactions (7)].

Concomitant use of XTAMPZA ER with CYP3A4 inducers or discontinuation of a 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 XTAMPZA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients 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)]

5.7 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect

[see Dependence (9.3)]

. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety)

[see Dosage and Administration (2.6), Warnings and Precautions (5.14)]

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

The use of XTAMPZA 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:

XTAMPZA 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 XTAMPZA 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 as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Regularly evaluate patients, particularly when initiating and titrating XTAMPZA ER and when XTAMPZA ER is given concomitantly with other drugs that depress respiration

[see Warnings and Precautions (5.2, 5.3)]

. Alternatively, consider the use of non-opioid analgesics in these patients. Use an alternative analgesic for patients who require a dose of XTAMPZA ER less than 9 mg.

5.9 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.

5.10 Severe Hypotension

XTAMPZA 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)]

. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of XTAMPZA ER. In patients with circulatory shock, XTAMPZA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of XTAMPZA ER in patients with circulatory shock.

5.11 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 CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), XTAMPZA ER may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with XTAMPZA ER.

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

5.12 Risks of Use in Patients with Gastrointestinal Conditions

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

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

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

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

5.14 Withdrawal

Do not abruptly discontinue XTAMPZA ER in a patient physically dependent on opioids. When discontinuing XTAMPZA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

[see Dosage and Administration (2.6), Drug Abuse and Dependence (9.3)]

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

[see Dosage and Administration (2.6), Drug Interactions (7)].

5.15 Risks of Driving and Operating Machinery

XTAMPZA 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 XTAMPZA ER and know how they will react to the medication.

5.16 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.

)
* Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

XTAMPZA ER is administered, twice daily, every 12 hours, and

must be taken with food.

Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved

[see Clinical Pharmacology (12.3)]

[see Dosage and Administration (2.7)].

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

5.1 Addiction, Abuse, and Misuse

XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse

[see Drug Abuse and Dependence (9)]

. Because extended-release products such as XTAMPZA 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)]

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death

[see Overdosage (10)].

).
* Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

XTAMPZA ER is administered, twice daily, every 12 hours, and

must be taken with food.

Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved

[see Clinical Pharmacology (12.3)]

[see Dosage and Administration (2.7)].

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential

[see Dosage and Administration (2)]

. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

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

Dosage and Administration (2.6)

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

)
* Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Consider prescribing naloxone based on the patient's risk factors for overdose. (

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

[see Warnings and Precautions (5.2)]

[see Warnings and Precautions (5.1, 5.2, 5.3)]

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

5.1 Addiction, Abuse, and Misuse

XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse

[see Drug Abuse and Dependence (9)]

. Because extended-release products such as XTAMPZA 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)]

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death

[see Overdosage (10)].

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential

[see Dosage and Administration (2)]

. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

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

Dosage and Administration (2.6)

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions (7)]

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]

[see Drug Interactions (7)

)
* For opioid-naïve and opioid non-tolerant patients, initiate with 9 mg (equivalent to 10 mg oxycodone HCl) capsules orally every 12 hours with food. (

2.3 Initial Dosing

Use of XTAMPZA ER as the First Opioid Analgesic (Opioid-Naïve Patients)

Initiate treatment with XTAMPZA ER with one 9 mg capsule orally every 12 hours with food.

Use of XTAMPZA ER in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is XTAMPZA ER 9 mg orally every 12 hours with food.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from other Oral Oxycodone Formulations to XTAMPZA ER

[see Dosage and Administration (2.1)].

Conversion from other Opioids to XTAMPZA ER

When XTAMPZA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There are no established conversion ratios for conversion from other opioids to XTAMPZA ER defined by clinical trials. Initiate dosing using XTAMPZA ER 9 mg orally every 12 hours with food.

Conversion from Methadone to XTAMPZA ER

Conversion from Transdermal Fentanyl to XTAMPZA ER

)
* 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). (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)].

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

XTAMPZA ER is administered, twice daily, every 12 hours, and

must be taken with food.

Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved

[see Clinical Pharmacology (12.3)]

[see Dosage and Administration (2.7)].

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)
*

Hepatic impairment

: Initiate therapy at 1/3 to 1/2 the usual dosage and titrate carefully. Regularly evaluate. Use alternate analgesia for patients requiring less than 9 mg. (

2.4 Dosage Modifications in Patients with Hepatic Impairment

[see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)]

8.6 Hepatic Impairment

A study in patients with hepatic impairment demonstrated greater plasma oxycodone concentrations than those seen at equivalent doses in persons with normal hepatic function. A similar effect on plasma oxycodone concentrations can be expected for patients with hepatic impairment taking XTAMPZA ER. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg

[see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]

)
* Do not abruptly discontinue XTAMPZA ER in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (

2.6 Safe Reduction or Discontinuation of XTAMPZA ER

[see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)]

5.14 Withdrawal

[see Dosage and Administration (2.6), Drug Abuse and Dependence (9.3)]

[see Dosage and Administration (2.6), Drug Interactions (7)].

)
* Instruct patients to take XTAMPZA ER capsules with food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, XTAMPZA ER can also be taken by sprinkling the capsule contents on soft foods or into a cup and then administering directly into the mouth, or through a gastrostomy or nasogastric feeding tube. (

2.7 Administration of XTAMPZA ER

Instruct patients to always take XTAMPZA ER capsules with food and with approximately the same amount of food in order to ensure consistent plasma levels are achieved

[see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]

The contents of the XTAMPZA ER capsules (microspheres) may be administered through a nasogastric tube or gastrostomy tube. When administering XTAMPZA ER through a nasogastric or gastrostomy tube:

Alternatively, milk or liquid nutritional supplement may be used as vehicles for flush and administration through feeding tubes.

)

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Xtampza ER Prescribing Information

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF XTAMPZA ER

See full prescribing information for complete boxed warning

XTAMPZA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing and reassess regularly for these behaviors and conditions. (
5.1 Addiction, Abuse, and Misuse
XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse
[see Drug Abuse and Dependence (9)]
. Because extended-release products such as XTAMPZA 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 XTAMPZA ER. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing XTAMPZA ER, and reassess all patients receiving XTAMPZA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol 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 XTAMPZA ER but use in such patients necessitates intensive counseling about the risks and proper use of XTAMPZA ER along with frequent evaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2)]
.
Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death
[see Overdosage (10)].
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing XTAMPZA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.
)
Serious, life-threatening, or fatal respiratory depression may occur especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential. (
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 XTAMPZA ER, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential
[see Dosage and Administration (2)]
. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see
Dosage and Administration (2.6)
].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [
see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
)
Accidental ingestion of XTAMPZA ER, especially by children, can result in fatal overdose of oxycodone. (
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 XTAMPZA ER, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential
[see Dosage and Administration (2)]
. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see
Dosage and Administration (2.6)
].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [
see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
)

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions (7)]

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]

[see Drug Interactions (7)

7 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 (5.6)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)] , 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. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved. Assess 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 (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.6)] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)] , 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 (2.5)] . Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider XTAMPZA ER dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.
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 [see Warnings and Precautions (5.3)] .
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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.3)] .
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, frequently evaluate 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 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 (5.2)].
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:	Because respiratory depression may be greater than otherwise expected, 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 (2.2), Warnings and Precautions (5.2, 5.3)].
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Evaluate 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:	Evaluate patients for signs of urinary retention or reduced gastric motility when XTAMPZA ER is used concomitantly with anticholinergic drugs.

CNS depressants
: Concomitant use may cause profound sedation, respiratory depression, coma, and death. If coadministration is required, consider dose reduction of one or both drugs because of additive pharmacological effects and frequently evaluate.
Serotonergic Drugs
: Concomitant use may result in serotonin syndrome. Discontinue XTAMPZA ER if serotonin syndrome is suspected.
Mixed agonist/antagonist and partial agonist opioid analgesics
: Avoid use with XTAMPZA ER because they may reduce analgesic effect of XTAMPZA ER or precipitate withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs)
: Can potentiate the effects of oxycodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI.

)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (
5.4 Neonatal Opioid Withdrawal Syndrome
Use of XTAMPZA ER for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
[see Use in Specific Populations (8.1)]
.
)
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (
5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Complete a
REMS-compliant education program
offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
)

Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone from XTAMPZA ER. (

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

[see Warnings and Precautions (5.2)]

[see Drug Interactions (7)].

[see Drug Interactions (7)]

12.3 Pharmacokinetics

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

Absorption

XTAMPZA ER is not bioequivalent to oxycodone extended-release tablets. In the fasted state, both peak serum concentration (C_max) and extent of absorption (AUC) are lower for XTAMPZA ER, and in the fed state, C_maxis lower, but AUC is similar.

Compared to immediate-release oxycodone solution dosed under fasted conditions the mean C_maxof oxycodone from XTAMPZA ER is lower (73% and 43% lower for fasted and fed administration, respectively) and the median time to peak plasma concentration (T_max) is approximately 3 hours longer. The extent of absorption of oxycodone from XTAMPZA ER is less than from immediate-release oxycodone oral solution in the fasted state (relative bioavailability of 75%), but comparable in the fed state (relatively bioavailability of 114%).

The peak plasma concentration of oxycodone from XTAMPZA ER occurs approximately 4.5 hours after fed dose administration. Upon repeated dosing with XTAMPZA ER in healthy subjects in pharmacokinetic studies, steady-state levels were achieved within 24-36 hours. Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. The apparent elimination half-life (t_½) of oxycodone following the administration of XTAMPZA ER when dosed in the fed state was 5.6 hours compared to 3.2 hours for immediate-release oxycodone.

Food Effects

The oral bioavailability of oxycodone from XTAMPZA ER is greater when taken with food than when taken in the fasted state. The oral bioavailability is dependent on the food consumed and is greatest following a high-fat and high-calorie meal with an increase in C_maxof 100-150% and AUC of 50-60% compared to the fasted state. Following a medium-fat medium-calorie meal, the C_maxincreased by 84% and AUC by 28% compared to the fasted state. Following a low-fat low-calorie meal, C_maxwas 19% higher and AUC was comparable, relative to the fasted state.

Pharmacokinetic Profile of XTAMPZA ER Intact and Sprinkled

Plasma concentration over time has been measured following administration of XTAMPZA ER capsule contents intact with food and sprinkled. The pharmacokinetic profile for the capsule contents sprinkled was equivalent to intact capsule administration (Table 7).

Table 7: Oxycodone Pharmacokinetic Parameters, Administration of Capsule Contents and Intact Capsules (36 mg)
Treatment	C_max (ng/mL)	T_max (hr)	AUC_0-INF (hr∙ng/mL)
Values shown for C_maxand AUC_0-INFare mean (standard deviation); values shown for T_maxare median (minimum – maximum).
Intact XTAMPZA ER Capsules (fed)	55.3 (13.6)	4.5 (1.5 – 9.0)	540 (143)
Sprinkled XTAMPZA ER Capsule Contents (fed)	48.1 (12.0)	4.5 (2.5 – 9.0)	528 (130)

Distribution

Following intravenous administration, the steady-state volume of distribution (V_ss) for oxycodone was 2.6 L/kg. Oxycodone binding to plasma protein at 37°C and a pH of 7.4 was about 45%. Once absorbed, oxycodone is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone has been found in breast milk

[see Use in Specific Populations (8.2)]

Elimination

In humans, oxycodone is extensively metabolized. Oxycodone and its metabolites are excreted primarily via the kidney.

Metabolism

Oxycodone is extensively metabolized by multiple metabolic pathways to produce noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. Noroxycodone and noroxymorphone are the major circulating metabolites. CYP3A mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a lower contribution from CYP2D6-mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs

[see Drug Interactions (7)]

Noroxycodone exhibits very weak anti-nociceptive potency compared to oxycodone; however, it undergoes further oxidation to produce noroxymorphone, which is active at opioid receptors. Although noroxymorphone is an active metabolite and present at relatively high concentrations in circulation, it does not appear to cross the blood-brain barrier to a significant extent. Oxymorphone is present in the plasma only at low concentrations and undergoes further metabolism to form its glucuronide and noroxymorphone. Oxymorphone has been shown to be active and to possess analgesic activity but its contribution to analgesia following oxycodone administration is thought to be clinically insignificant. Other metabolites (α- and ß-oxycodol, noroxycodol, and oxymorphol) may be present at very low concentrations and demonstrate limited penetration into the brain as compared to oxycodone. The enzymes responsible for keto-reduction and glucuronidation pathways in oxycodone metabolism have not been established.

Excretion

Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free and conjugated oxycodone 8.9%, free noroxycodone 23%, free oxymorphone less than 1%, conjugated oxymorphone 10%, free and conjugated noroxymorphone 14%, reduced free and conjugated metabolites up to 18%. The total plasma clearance was approximately 1.4 L/min in adults.

Specific Populations

Age: Geriatric Population

The plasma concentrations of oxycodone are nominally affected by age, being 15% greater in elderly as compared to young subjects (age 21-45).

Sex

Across individual pharmacokinetic studies, oxycodone plasma exposures for female subjects were up to 20% higher than for male subjects, even after considering differences in body weight or BMI. The reason for this difference is unknown

[see Use in Specific Populations (8)]

Renal Impairment

Data from a pharmacokinetic study involving 13 patients with mild to severe renal dysfunction (creatinine clearance <60 mL/min) showed peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, and AUC values for oxycodone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than normal subjects, respectively. This was accompanied by an increase in sedation, but not by differences in respiratory rate, pupillary constriction, or several other measures of drug effect. There was an increase in mean elimination t_½for oxycodone of 1 hour.

Hepatic Impairment

Data from a study involving 24 patients with mild to moderate hepatic dysfunction show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, than healthy subjects. AUC values are 95% and 65% higher, respectively. Oxymorphone peak plasma concentrations and AUC values are lower by 30% and 40%. The mean elimination t_½for oxycodone increased by 2.3 hours.

Drug Interaction Studies

CYP3A4 Inhibitors

CYP3A4 is the major enzyme involved in noroxycodone formation. Co-administration of a 10 mg single dose of oxycodone extended –release tablet and the CYP3A4 inhibitor ketoconazole (200 mg BID) increased oxycodone AUC and C_maxby 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 C_maxvalues 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 is not expected to be of clinical significance for XTAMPZA ER

[see Drug Interactions (7)]

)

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF XTAMPZA ER

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF XTAMPZA ER

See full prescribing information for complete boxed warning

XTAMPZA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk before prescribing and reassess regularly for these behaviors and conditions.
Serious, life-threatening, or fatal respiratory depression may occur especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential.
Accidental ingestion of XTAMPZA ER, especially by children, can result in fatal overdose of oxycodone.
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate.
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.
Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone from XTAMPZA ER.

Addiction, Abuse, and Misuse

Because the use of XTAMPZA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions

[see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of XTAMPZA ER, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential

[see Warnings and Precautions (5.2)].

Accidental Ingestion

Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in a fatal overdose of oxycodone

[see Warnings and Precautions (5.2)]

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of XTAMPZA ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

[see Warnings and Precautions (5.3), Drug Interactions (7)]

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery

[see Warnings and Precautions (5.4)]

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription

[see Warnings and Precautions (5.5)]

Cytochrome P450 3A4 Interaction

The concomitant use of XTAMPZA ER with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving XTAMPZA ER and any CYP3A4 inhibitor or inducer

[see Warnings and Precautions (5.6), Drug Interactions (7), Clinical Pharmacology (12.3)]

12/2023

Indications and Usage (

1 INDICATIONS AND USAGE

XTAMPZA ER is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

XTAMPZA ER is an opioid agonist indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, reserve XTAMPZA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
XTAMPZA ER is not indicated as an as-needed (prn) analgesic.

Limitations of Use

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

)

12/2023

Dosage and Administration (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

2.3 Initial Dosing

Use of XTAMPZA ER as the First Opioid Analgesic (Opioid-Naïve Patients)

Initiate treatment with XTAMPZA ER with one 9 mg capsule orally every 12 hours with food.

Use of XTAMPZA ER in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is XTAMPZA ER 9 mg orally every 12 hours with food.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from other Oral Oxycodone Formulations to XTAMPZA ER

[see Dosage and Administration (2.1)].

Conversion from other Opioids to XTAMPZA ER

When XTAMPZA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There are no established conversion ratios for conversion from other opioids to XTAMPZA ER defined by clinical trials. Initiate dosing using XTAMPZA ER 9 mg orally every 12 hours with food.

Conversion from Methadone to XTAMPZA ER

Conversion from Transdermal Fentanyl to XTAMPZA ER

2.5 Titration and Maintenance of Therapy

[see Warnings and Precautions (5)]

. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

)

12/2023

Warnings and Precautions (

5.7 Opioid-Induced Hyperalgesia and Allodynia

[see Dependence (9.3)]

[see Dosage and Administration (2.6), Warnings and Precautions (5.14)]

)

12/2023

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)

XTAMPZA ER at a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone hydrochloride [HCl]) or a single dose greater than 36 mg (equivalent to 40 mg oxycodone HCl) is only for use in patients in whom tolerance to an opioid of comparable potency has been established. (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)

Patients considered 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 HCl 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. (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)

Use the lowest effective dose for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (

2 DOSAGE AND ADMINISTRATION

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER at a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone hydrochloride [HCl]) or a single dose greater than 36 mg (equivalent to 40 mg oxycodone HCl) is only for use in patients in whom tolerance to an opioid of comparable potency has been established.
Patients considered 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 HCl 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 dose for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse .
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Consider prescribing naloxone based on the patient's risk factors for overdose.
For opioid-naïve and opioid non-tolerant patients, initiate with 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).
Hepatic impairment
: Initiate therapy at 1/3 to 1/2 the usual dosage and titrate carefully. Regularly evaluate. Use alternate analgesia for patients requiring less than 9 mg.
Do not abruptly discontinue XTAMPZA ER in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.
Instruct patients to take XTAMPZA ER capsules with food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, XTAMPZA ER can also be taken by sprinkling the capsule contents on soft foods or into a cup and then administering directly into the mouth, or through a gastrostomy or nasogastric feeding tube.

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

[see Warnings and Precautions (5.2)]

[see Warnings and Precautions (5.1, 5.2, 5.3)]

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

2.3 Initial Dosing

Use of XTAMPZA ER as the First Opioid Analgesic (Opioid-Naïve Patients)

Initiate treatment with XTAMPZA ER with one 9 mg capsule orally every 12 hours with food.

Use of XTAMPZA ER in Patients who are not Opioid Tolerant

The starting dose for patients who are not opioid tolerant is XTAMPZA ER 9 mg orally every 12 hours with food.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from other Oral Oxycodone Formulations to XTAMPZA ER

[see Dosage and Administration (2.1)].

Conversion from other Opioids to XTAMPZA ER

When XTAMPZA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There are no established conversion ratios for conversion from other opioids to XTAMPZA ER defined by clinical trials. Initiate dosing using XTAMPZA ER 9 mg orally every 12 hours with food.

Conversion from Methadone to XTAMPZA ER

Conversion from Transdermal Fentanyl to XTAMPZA ER

2.4 Dosage Modifications in Patients with Hepatic Impairment

[see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)]

2.5 Titration and Maintenance of Therapy

[see Warnings and Precautions (5)]

. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.6 Safe Reduction or Discontinuation of XTAMPZA ER

[see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)]

2.7 Administration of XTAMPZA ER

Instruct patients to always take XTAMPZA ER capsules with food and with approximately the same amount of food in order to ensure consistent plasma levels are achieved

[see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]

Open the capsule.
Sprinkle the capsule contents (microspheres) onto a small amount of soft food (e.g., applesauce, pudding, yogurt, ice cream, or jam) or into a cup and then administer directly into the mouth and swallow immediately.
Rinse the mouth to ensure all capsule contents (microspheres) have been swallowed.
Discard the XTAMPZA ER capsule shells after the contents have been sprinkled on soft food or into a cup and then administered directly into the mouth.

The contents of the XTAMPZA ER capsules (microspheres) may be administered through a nasogastric tube or gastrostomy tube. When administering XTAMPZA ER through a nasogastric or gastrostomy tube:

Flush the tube with water.
Open an XTAMPZA ER capsule and carefully pour the microspheres directly into the tube. Do not pre-mix the capsule contents with the liquid that you will be using to flush them through the tube.
Draw up 15 mL of water into a syringe, insert the syringe into the tube, and flush the microspheres through the tube.
Repeat the flushing two more times, each with 10 mL of water, to ensure no microspheres remain in the tube.

Alternatively, milk or liquid nutritional supplement may be used as vehicles for flush and administration through feeding tubes.

5 WARNINGS AND PRECAUTIONS

Opioid-Induced Hyperalgesia and Allodynia
: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation.
Risk of life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients
: Regularly evaluate.
Adrenal Insufficiency
: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
Severe hypotension
: Regularly evaluate. Avoid use of XTAMPZA ER in patients with circulatory shock.
Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness
: Monitor for sedation and respiratory depression. Avoid use of XTAMPZA ER in patients with impaired consciousness or coma.

5.1 Addiction, Abuse, and Misuse

XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse

[see Drug Abuse and Dependence (9)]

. Because extended-release products such as XTAMPZA 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)]

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death

[see Overdosage (10)].

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential

[see Dosage and Administration (2)]

. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

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

Dosage and Administration (2.6)

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions (7)]

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]

[see Drug Interactions (7)

5.4 Neonatal Opioid Withdrawal Syndrome

[see Use in Specific Populations (8.1)]

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Complete a
REMS-compliant education program
offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

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

[see Warnings and Precautions (5.2)]

[see Drug Interactions (7)].

[see Drug Interactions (7)]

5.7 Opioid-Induced Hyperalgesia and Allodynia

[see Dependence (9.3)]

[see Dosage and Administration (2.6), Warnings and Precautions (5.14)]

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

The use of XTAMPZA 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:

see Warnings and Precautions (5.2)

Elderly, Cachectic, or Debilitated Patients:

Regularly evaluate patients, particularly when initiating and titrating XTAMPZA ER and when XTAMPZA ER is given concomitantly with other drugs that depress respiration

[see Warnings and Precautions (5.2, 5.3)]

. Alternatively, consider the use of non-opioid analgesics in these patients. Use an alternative analgesic for patients who require a dose of XTAMPZA ER less than 9 mg.

5.9 Adrenal Insufficiency

5.10 Severe Hypotension

[see Drug Interactions (7)]

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

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

5.12 Risks of Use in Patients with Gastrointestinal Conditions

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

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

5.14 Withdrawal

[see Dosage and Administration (2.6), Drug Abuse and Dependence (9.3)]

[see Dosage and Administration (2.6), Drug Interactions (7)].

5.15 Risks of Driving and Operating Machinery

5.16 Laboratory Monitoring

)

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

5.1 Addiction, Abuse, and Misuse

XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse

[see Drug Abuse and Dependence (9)]

. Because extended-release products such as XTAMPZA 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)]

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)]

Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death

[see Overdosage (10)].

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential

[see Dosage and Administration (2)]

. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

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

Dosage and Administration (2.6)

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

)

Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Consider prescribing naloxone based on the patient's risk factors for overdose. (
2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER
[see Warnings and Precautions (5.2)]
.
Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient
[see Warnings and Precautions (5.1, 5.2, 5.3)]
.
Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.
,
5.1 Addiction, Abuse, and Misuse
XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse
[see Drug Abuse and Dependence (9)]
. Because extended-release products such as XTAMPZA 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 XTAMPZA ER. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing XTAMPZA ER, and reassess all patients receiving XTAMPZA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol 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 XTAMPZA ER but use in such patients necessitates intensive counseling about the risks and proper use of XTAMPZA ER along with frequent evaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2)]
.
Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death
[see Overdosage (10)].
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing XTAMPZA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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 XTAMPZA ER, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential
[see Dosage and Administration (2)]
. Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see
Dosage and Administration (2.6)
].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with XTAMPZA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [
see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
,
5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of XTAMPZA ER with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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 depressants 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]
.
Advise both patients and caregivers about the risks of respiratory depression and sedation when XTAMPZA 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)
.
)
For opioid-naïve and opioid non-tolerant patients, initiate with 9 mg (equivalent to 10 mg oxycodone HCl) capsules orally every 12 hours with food. (
2.3 Initial Dosing
Use of XTAMPZA ER as the First Opioid Analgesic (Opioid-Naïve Patients)
Initiate treatment with XTAMPZA ER with one 9 mg capsule orally every 12 hours with food.
Use of XTAMPZA ER in Patients who are not Opioid Tolerant
The starting dose for patients who are not opioid tolerant is XTAMPZA ER 9 mg orally every 12 hours with food.
Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression
[see Warnings and Precautions (5.2)]
.
Conversion from other Oral Oxycodone Formulations to XTAMPZA ER
Patients receiving other oral oxycodone formulations may be converted to XTAMPZA ER, using the same total daily dose of oxycodone, by administering one-half of the patient's total daily oral oxycodone dose as XTAMPZA ER every 12 hours with food. Because XTAMPZA ER is not bioequivalent to other oxycodone extended-release products, monitor patients for possible dosage adjustment
[see Dosage and Administration (2.1)].
Conversion from other Opioids to XTAMPZA ER
When XTAMPZA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.
There are no established conversion ratios for conversion from other opioids to XTAMPZA ER defined by clinical trials. Initiate dosing using XTAMPZA ER 9 mg orally every 12 hours with food.
It is safer to underestimate a patient's 24-hour oral oxycodone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxycodone dosage and manage adverse reactions due to an overdose. While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products.
Conversion from Methadone to XTAMPZA ER
Frequent evaluation 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 XTAMPZA ER
Eighteen hours following the removal of the transdermal fentanyl patch, XTAMPZA ER treatment can be initiated. Although there has been no systematic assessment of such conversion, a conservative oxycodone dose, approximately 9 mg (equivalent to 10 mg oxycodone HCl) every 12 hours of XTAMPZA ER, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient closely during conversion from transdermal fentanyl to XTAMPZA ER, as there is limited documented experience with this conversion.
)

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). (

2.1 Important Dosage and Administration Instructions

XTAMPZA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
XTAMPZA ER single doses greater than 36 mg (equivalent to 40 mg oxycodone hydrochloride [HCl]) or a total daily dose greater than 72 mg (equivalent to 80 mg oxycodone HCl) are to be administered only to 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 HCl 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 of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)].
Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of XTAMPZA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with XTAMPZA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
XTAMPZA ER is administered, twice daily, every 12 hours, and
must be taken with food.
Instruct patients to take XTAMPZA ER capsules with approximately the same amount of food for every dose in order to ensure consistent plasma levels are achieved
[see Clinical Pharmacology (12.3)]
.
Patients who are unable to swallow XTAMPZA ER should be instructed to sprinkle the capsule contents on soft foods or into a cup and then administer directly into the mouth and immediately swallow. XTAMPZA ER may also be administered through a gastrostomy or nasogastric feeding tube
[see Dosage and Administration (2.7)].
The maximum daily dose of XTAMPZA ER is 288 mg per day (eight 36 mg capsules, equivalent to 320 mg oxycodone HCl per day) as the safety of the excipients in XTAMPZA ER for doses over 288 mg/day has not been established.
XTAMPZA ER is formulated with oxycodone base. The following table describes the equivalent amount of oxycodone HCl present in other oxycodone products.

Equivalence table for dosage strengths of oxycodone hydrochloride salt and oxycodone base (XTAMPZA ER)
Oxycodone Hydrochloride	Oxycodone base (XTAMPZA ER)
10 mg	9 mg
15 mg	13.5 mg
20 mg	18 mg
30 mg	27 mg
40 mg	36 mg

)

Hepatic impairment
: Initiate therapy at 1/3 to 1/2 the usual dosage and titrate carefully. Regularly evaluate. Use alternate analgesia for patients requiring less than 9 mg. (
2.4 Dosage Modifications in Patients with Hepatic Impairment
For patients with hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration. Regularly evaluate for adverse events such as respiratory depression. Use of alternate analgesics is recommended for patients who require an XTAMPZA ER dose of less than 9 mg
[see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)]
.
,
8.6 Hepatic Impairment
A study in patients with hepatic impairment demonstrated greater plasma oxycodone concentrations than those seen at equivalent doses in persons with normal hepatic function. A similar effect on plasma oxycodone concentrations can be expected for patients with hepatic impairment taking XTAMPZA ER. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg
[see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]
.
)
Do not abruptly discontinue XTAMPZA ER in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
2.6 Safe Reduction or Discontinuation of XTAMPZA ER
Do not abruptly discontinue XTAMPZA ER in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in 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. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking XTAMPZA ER, there are a variety of factors that should be considered, including the total daily dose of opioid (including XTAMPZA ER) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on XTAMPZA ER who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic
[see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)]
.
,
5.14 Withdrawal
Do not abruptly discontinue XTAMPZA ER in a patient physically dependent on opioids. When discontinuing XTAMPZA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
[see Dosage and Administration (2.6), Drug Abuse and Dependence (9.3)]
.
Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including XTAMPZA ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms
[see Dosage and Administration (2.6), Drug Interactions (7)].
)
Instruct patients to take XTAMPZA ER capsules with food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, XTAMPZA ER can also be taken by sprinkling the capsule contents on soft foods or into a cup and then administering directly into the mouth, or through a gastrostomy or nasogastric feeding tube. (
2.7 Administration of XTAMPZA ER
Instruct patients to always take XTAMPZA ER capsules with food and with approximately the same amount of food in order to ensure consistent plasma levels are achieved
[see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]
.
For patients who have difficulty swallowing, XTAMPZA ER can also be taken by sprinkling the capsule contents on soft foods or sprinkling the contents into a cup and then administering directly into the mouth or through a gastrostomy or nasogastric feeding tube. Patients who are unable to swallow a capsule should be instructed to:
- Open the capsule.
- Sprinkle the capsule contents (microspheres) onto a small amount of soft food (e.g., applesauce, pudding, yogurt, ice cream, or jam) or into a cup and then administer directly into the mouth and swallow immediately.
- Rinse the mouth to ensure all capsule contents (microspheres) have been swallowed.
- Discard the XTAMPZA ER capsule shells after the contents have been sprinkled on soft food or into a cup and then administered directly into the mouth.
The contents of the XTAMPZA ER capsules (microspheres) may be administered through a nasogastric tube or gastrostomy tube. When administering XTAMPZA ER through a nasogastric or gastrostomy tube:
- Flush the tube with water.
- Open an XTAMPZA ER capsule and carefully pour the microspheres directly into the tube. Do not pre-mix the capsule contents with the liquid that you will be using to flush them through the tube.
- Draw up 15 mL of water into a syringe, insert the syringe into the tube, and flush the microspheres through the tube.
- Repeat the flushing two more times, each with 10 mL of water, to ensure no microspheres remain in the tube.
Alternatively, milk or liquid nutritional supplement may be used as vehicles for flush and administration through feeding tubes.
)

XTAMPZA ER capsules contain yellow to light brown microspheres, and each available strength has an outer opaque capsule with colors as identified below.

Strength	Capsule Description
9 mg (equivalent to 10 mg oxycodone HCl)	Size 3, ivory cap printed with "XTAMPZA ER" and white body printed with "9 mg"
13.5 mg (equivalent to 15 mg oxycodone HCl)	Size 2, Swedish orange cap printed with "XTAMPZA ER" and white body printed with "13.5 mg"
18 mg (equivalent to 20 mg oxycodone HCl)	Size 1, rich yellow cap printed with "XTAMPZA ER" and white body printed with "18 mg"
27 mg (equivalent to 30 mg oxycodone HCl)	Size 0, light gray cap printed with "XTAMPZA ER" and white body printed with "27 mg"
36 mg (equivalent to 40 mg oxycodone HCl)	Size 00, flesh color cap printed with "XTAMPZA ER" and white body printed with "36 mg"

Pregnancy:
May cause fetal harm. (
8.1 Pregnancy
Risk Summary
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome
[see Warnings and Precautions (5.4)]
. There are no available data with XTAMPZA ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, there was no embryo-fetal toxicity when oxycodone hydrochloride was orally administered to rats and rabbits, during the period of organogenesis, at doses 1.3 to 40 times the adult human dose of 60 mg/day, respectively. In a pre- and postnatal toxicity study, when oxycodone was orally administered to rats, there was transiently decreased pup body weight during lactation and the early post-weaning period at the dose equivalent to an adult dose of 160 mg/day. 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 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 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/neonatal adverse reactions
Use of opioid analgesics for an extended period of time 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 of use, and severity of neonatal opioid withdrawal syndrome may 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 (5.4)]
.
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 opioid induced respiratory depression in the neonate. XTAMPZA ER is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including XTAMPZA 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Data
Animal Data
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 1.3 and 40 times an adult human dose of 160 mg/day, respectively on a mg/m²basis, 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 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 dams given the highest dose used (6 mg/kg/day, equivalent to an adult human dose of 160 mg/day, on a mg/m²basis). 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/m²basis), 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/m²basis).
)
Lactation:
Not recommended. (
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 extended–release oxycodone, including XTAMPZA ER, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. 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 XTAMPZA ER.
Clinical Considerations
Monitor infants exposed to XTAMPZA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
)

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