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| Product NDC Code | 24510-140 | ||||||
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| Drug Name | Xtampza er |
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| Type | Brand | ||||||
| Pharm Class | Full Opioid Agonists [MoA], Opioid Agonist [EPC] |
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| Active Ingredients |
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| Route | ORAL | ||||||
| Dosage Form | CAPSULE, EXTENDED RELEASE | ||||||
| RxCUI drug identifier | 1790527, 1790533, 1791558, 1791560, 1791567, 1791569, 1791574, 1791576, 1791580, 1791582 |
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| Application Number | NDA208090 | ||||||
| Labeler Name | Collegium Pharmaceutical, Inc. | ||||||
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Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse XTAMPZA ER contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of XTAMPZA ER increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of XTAMPZA ER with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of XTAMPZA ER abuse include those with a history of prolonged use of any opioid, including products containing buprenorphine, those with a history of drug or alcohol abuse, or those who use XTAMPZA ER in combination with other abused drugs. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. XTAMPZA ER, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of XTAMPZA ER Abuse of XTAMPZA ER poses a risk of overdose and death. The risk is increased with concurrent use of XTAMPZA ER with alcohol and/or other CNS depressants [ see Warnings and Precautions (5.1 , 5.3) , Drug Interactions (7) ] . XTAMPZA ER is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Abuse Deterrence Studies XTAMPZA ER capsules contain microspheres formulated with inactive ingredients intended to make the formulation more difficult to manipulate for misuse and abuse. In Vitro Testing In vitro physical and chemical manipulation studies were performed to evaluate the success of different methods of defeating the extended-release formulation. Results support that, relative to immediate-release oxycodone tablets, XTAMPZA ER is less susceptible to the effects of grinding, crushing, and extraction using a variety of tools and solvents. XTAMPZA ER resisted attempts to pass the melted capsule contents or the microspheres suspended in water through a hypodermic needle. Pharmacokinetic Studies The pharmacokinetic profile of manipulated XTAMPZA ER capsule contents (36 mg; [equivalent to 40 mg oxycodone HCl]) was characterized following oral (three studies) and intranasal (two studies) administration. The studies were conducted in a randomized, cross-over design. In studies assessing manipulation by crushing, the most effective crushing method identified in previous in vitro studies was applied to the product(s). Oral Pharmacokinetic Studies, Manipulated and Intact XTAMPZA ER The effect of two types of product manipulation (crushing and chewing) on XTAMPZA ER pharmacokinetics was measured in three studies. In one oral pharmacokinetic study, XTAMPZA ER capsule contents were crushed or chewed prior to oral administration in healthy, naltrexone-blocked volunteers. The two comparators in this study were intact XTAMPZA ER capsules and an immediate-release solution of oxycodone at an equivalent dose. In two oral pharmacokinetic studies, XTAMPZA ER capsule contents were crushed prior to oral administration in healthy, naltrexone-blocked volunteers. The comparators in these studies included intact XTAMPZA ER capsules, intact and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets at an equivalent dose, and crushed immediate-release oxycodone tablets at an equivalent dose. The data displayed in Table 3 illustrate the findings from the oral pharmacokinetic studies (data were similar for the two oral pharmacokinetic studies comparing XTAMPZA ER to OXYCONTIN). Collectively, the data demonstrated that crushing or chewing XTAMPZA ER prior to administration did not increase the maximum observed plasma concentration (C max ) or total exposure (AUC 0-INF ) relative to dosing the intact product under fed conditions. Relative to immediate-release oxycodone and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets, the C max for all XTAMPZA ER treatments was lower and the T max longer, consistent with an extended-release profile. Table 3: Oxycodone Pharmacokinetic Parameters, Administration of Manipulated and Intact Dosage Forms (36 mg of XTAMPZA ER or equivalent) C max (ng/mL) T max (hr) AUC 0-INF (hr∙ng/mL) Values shown for C max and AUC 0-INF are mean (standard deviation); values shown for T max are median (minimum-maximum). Treatment Oral Pharmacokinetic Study 1 Intact XTAMPZA ER Capsules (fed) 62.3 (13.0) 4.0 (1.5-6) 561 (124) Crushed XTAMPZA ER Capsule Contents (fed) 57.6 (12.6) 4.5 (2.5-6) 553 (134) Chewed XTAMPZA ER Capsule Contents (fed) 55.6 (10.9) 4.5 (2.5-8) 559 (113) Immediate-Release Oxycodone Solution (fasted) 115 (27.3) 0.75 (0.5-2) 489 (80.2) Oral Pharmacokinetic Study 2 Intact XTAMPZA ER Capsules (fed) 67.5 (17.6) 3.5 (1.25-6.0) 581 (138) Crushed XTAMPZA ER Capsule Contents (fed) 62.9 (12.6) 4.0 (2.0-7.0) 597 (149) Intact reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) 64.9 (13.8) 5.0 (2.0-10.0) 611 (145) Crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) 78.4 (12.9) 1.75 (0.5-5.0) 587 (132) Crushed Immediate-Release Oxycodone Tablets (fed) 79.4 (17.1) 1.75 (0.5-4.0) 561 (146) Nasal Pharmacokinetic Studies The pharmacokinetic profile following intranasal administration of crushed XTAMPZA ER capsule contents was characterized in two clinical studies. In Nasal Pharmacokinetic Study 1, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent, naltrexone-blocked subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and oxycodone HCl powder (intranasal) at an equivalent dose. In Nasal Pharmacokinetic Study 2, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and crushed oxycodone immediate-release tablets (intranasal) at an equivalent dose. The results of Nasal Pharmacokinetic Studies 1 and 2 are comparable and both studies demonstrated that intranasal administration of crushed XTAMPZA ER capsule contents did not result in higher peak plasma concentration (C max ) or shorter time to peak concentration (T max ) than taking XTAMPZA ER orally. The data from Nasal Pharmacokinetic Study 2 are displayed in Table 4 to represent these findings. Table 4: Oxycodone Pharmacokinetic Parameters, Nasal Pharmacokinetic Study 2: Treatment C max (ng/mL) T max (hr) AUC 0-INF (hr∙ng/mL) Values shown for C max and AUC 0-INF are mean (standard deviation); values shown for T max are median (minimum-maximum). Intact XTAMPZA ER Capsules (oral) 41.0 (10.0) 5.1 (1.6-8.1) 477 (89.6) Crushed XTAMPZA ER Capsule Contents (nasal) 29.8 (6.6) 5.1 (1.6-12.1) 459 (106) Crushed Immediate-Release Tablets (nasal) 60.9 (11.9) 2.6 (0.3-6.1) 577 (124) Clinical Studies Oral Abuse Potential Studies: The oral abuse potential of chewed XTAMPZA ER was evaluated in two studies. In a randomized, double-blind, active- and placebo-controlled, single-dose, six-way crossover pharmacodynamic study, 52 non-dependent recreational opioid users received orally-administered active and placebo treatment. The six treatment arms were intact XTAMPZA ER (36 mg, fed and fasted); chewed XTAMPZA ER (36 mg, fed and fasted); crushed immediate-release (IR) oxycodone HCl in solution (40 mg, fasted, equivalent to 36 mg of XTAMPZA ER), and placebo. Data for chewed and intact XTAMPZA ER and crushed IR oxycodone in the fasted state are described below. Drug Liking was measured on a bipolar 100-point Visual Analog Scale (VAS) where 50 represents a neutral response, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar 100-point VAS where 50 represents a neutral response, 0 represents the strongest negative response (e.g., 'definitely would not take drug again'), and 100 represents the strongest positive response (e.g., 'definitely would take drug again'). Fifty-two subjects completed the study, and the results are summarized in Table 5. The oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking and Take Drug Again VAS scores compared with crushed immediate-release oxycodone. In addition, the Drug Liking and Take Drug Again scores were similar for XTAMPZA ER taken in the intact and chewed states. Table 5: Summary of Maximum Drug Liking and Take Drug Again (E max ) Following Oral Administration XTAMPZA ER Intact (Fasted) XTAMPZA ER Chewed (Fasted) Crushed IR Oxycodone (Fasted) Placebo Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) (E max ) Mean (SD) 73.9 (15.10) 73.3 (14.93) 86.40 (12.01) 55.8 (9.94) Median (Range) 73.5 (50-100) 73.5 (50-100) 88.5 (52-100) 50.0 (50-86) Take Drug Again (E max ) Mean (SD) 77.98 (21.07) 77.85 (18.30) 87.69 (12.90) 50.79 (21.41) Median (Range) 80.5 (1-100) 81.5 (50-100) 90.5 (50-100) 50.0 (0-100) A prior, similarly-designed study was also conducted to evaluate the oral abuse potential of chewed XTAMPZA ER. Although the oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking scores compared with crushed immediate-release oxycodone, the results for Take Drug Again showed small differences that were not statistically significant. Nasal Abuse Potential Study: In a randomized, double-blind, active- and placebo-controlled, single-dose, four-way crossover pharmacodynamic study, 39 recreational opioid users with a history of intranasal drug abuse received nasally administered active and placebo drug treatment. The four treatment arms were crushed XTAMPZA ER 36 mg dosed intranasally; intact XTAMPZA ER 36 mg dosed orally; crushed immediate-release oxycodone HCl 40 mg (equivalent to 36 mg of XTAMPZA ER) dosed intranasally; and placebo. Data for intranasal XTAMPZA ER and crushed immediate-release oxycodone are described below. Thirty-six subjects completed the study. Intranasal administration of crushed XTAMPZA ER was associated with statistically lower mean Drug Liking and Take Drug Again scores compared with crushed immediate-release oxycodone (summarized in Table 6). Table 6: Summary of Maximum Drug Liking and Take Drug Again (E max ) Following Intranasal Administration XTAMPZA ER Intranasal Crushed IR Oxycodone Intranasal Placebo E max = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response). (E max ) Mean (SD) 61.81 (15.64) 82.72 (10.95) 54.5 (11.77) Median (Range) 59.5 (16-94) 84 (60-100) 51 (28-93) Take Drug Again (E max ) Mean (SD) 47.67 (27.84) 71.36 (23.49) 45.92 (17.50) Median (Range) 50 (0-100) 78.5 (18-100) 50 (0-97) Figure 1 demonstrates a comparison of Drug Liking for intranasal administration of crushed XTAMPZA ER compared to crushed immediate-release oxycodone in subjects who received both treatments (N=36). The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for XTAMPZA ER vs. immediate-release oxycodone greater than or equal to the value on the X-axis. Approximately 92% (n = 33) of subjects had some reduction in drug liking with XTAMPZA ER relative to crushed immediate-release oxycodone HCl. Approximately 78% (n = 28) of subjects had a reduction of at least 30% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl, and approximately 58% (n = 21) of subjects had a reduction of at least 50% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl. Figure 1: Percent Reduction Profiles for E max of Drug Liking VAS for Crushed XTAMPZA ER vs. Crushed Immediate-release Oxycodone, N=36 Following Intranasal Administration Figure 1 Summary The in vitro data demonstrate that XTAMPZA ER has physicochemical properties expected to make abuse by injection difficult. The data from pharmacokinetic and human abuse potential studies, along with support from the in vitro data, also indicate that XTAMPZA ER has physicochemical properties that are expected to reduce abuse via the oral and intranasal routes. The data from the oral pharmacokinetic studies of crushed or chewed XTAMPZA ER demonstrated a lack of dose dumping with no increase in oxycodone levels compared to intact XTAMPZA ER. However, abuse of XTAMPZA ER by injection and by the oral and nasal routes of administration is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of XTAMPZA ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. XTAMPZA ER contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.3) ] .
| Cmax (ng/mL) | Tmax (hr) | AUC0-INF (hr∙ng/mL) | |
|---|---|---|---|
| Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum). | |||
| Intact XTAMPZA ER Capsules (fed) | 62.3 (13.0) | 4.0 (1.5-6) | 561 (124) |
| Crushed XTAMPZA ER Capsule Contents (fed) | 57.6 (12.6) | 4.5 (2.5-6) | 553 (134) |
| Chewed XTAMPZA ER Capsule Contents (fed) | 55.6 (10.9) | 4.5 (2.5-8) | 559 (113) |
| Immediate-Release Oxycodone Solution (fasted) | 115 (27.3) | 0.75 (0.5-2) | 489 (80.2) |
| Intact XTAMPZA ER Capsules (fed) | 67.5 (17.6) | 3.5 (1.25-6.0) | 581 (138) |
| Crushed XTAMPZA ER Capsule Contents (fed) | 62.9 (12.6) | 4.0 (2.0-7.0) | 597 (149) |
| Intact reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) | 64.9 (13.8) | 5.0 (2.0-10.0) | 611 (145) |
| Crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) | 78.4 (12.9) | 1.75 (0.5-5.0) | 587 (132) |
| Crushed Immediate-Release Oxycodone Tablets (fed) | 79.4 (17.1) | 1.75 (0.5-4.0) | 561 (146) |
| Treatment | Cmax (ng/mL) | Tmax (hr) | AUC0-INF (hr∙ng/mL) |
|---|---|---|---|
| Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum). | |||
| Intact XTAMPZA ER Capsules (oral) | 41.0 (10.0) | 5.1 (1.6-8.1) | 477 (89.6) |
| Crushed XTAMPZA ER Capsule Contents (nasal) | 29.8 (6.6) | 5.1 (1.6-12.1) | 459 (106) |
| Crushed Immediate-Release Tablets (nasal) | 60.9 (11.9) | 2.6 (0.3-6.1) | 577 (124) |
| XTAMPZA ER Intact (Fasted) | XTAMPZA ER Chewed (Fasted) | Crushed IR Oxycodone (Fasted) | Placebo | ||
|---|---|---|---|---|---|
| Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. | |||||
| Drug Liking | Mean (SD) | 73.9 (15.10) | 73.3 (14.93) | 86.40 (12.01) | 55.8 (9.94) |
| Median (Range) | 73.5 (50-100) | 73.5 (50-100) | 88.5 (52-100) | 50.0 (50-86) | |
| Take Drug Again (Emax) | Mean (SD) | 77.98 (21.07) | 77.85 (18.30) | 87.69 (12.90) | 50.79 (21.41) |
| Median (Range) | 80.5 (1-100) | 81.5 (50-100) | 90.5 (50-100) | 50.0 (0-100) | |
| XTAMPZA ER Intranasal | Crushed IR Oxycodone Intranasal | Placebo | ||
|---|---|---|---|---|
| Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. | ||||
| Drug Liking | Mean (SD) | 61.81 (15.64) | 82.72 (10.95) | 54.5 (11.77) |
| Median (Range) | 59.5 (16-94) | 84 (60-100) | 51 (28-93) | |
| Take Drug Again | Mean (SD) | 47.67 (27.84) | 71.36 (23.49) | 45.92 (17.50) |
| Median (Range) | 50 (0-100) | 78.5 (18-100) | 50 (0-97) | |
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance XTAMPZA ER contains oxycodone, a Schedule II controlled substance.
Dependence
Information about characteristic effects resulting from both psychological and physical dependence that occur with the drug, the quantity of drug over a period of time that may lead to tolerance or dependence, details of adverse effects related to chronic abuse and the effects of abrupt withdrawl, procedures necessary to diagnose the dependent state, and principles of treating the effects of abrupt withdrawal.9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not abruptly discontinue XTAMPZA ER in a patient physically dependent on opioids. Rapid tapering of XTAMPZA ER in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing XTAMPZA ER, gradually taper the dosage using a patient-specific plan that considers the following: the dose of XTAMPZA ER the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [ see Dosage and Administration (2.6) , Warnings and Precautions (5.14) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [ see Use in Specific Populations (8.1) ].
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance XTAMPZA ER contains oxycodone, a Schedule II controlled substance. 9.2 Abuse XTAMPZA ER contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of XTAMPZA ER increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of XTAMPZA ER with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of XTAMPZA ER abuse include those with a history of prolonged use of any opioid, including products containing buprenorphine, those with a history of drug or alcohol abuse, or those who use XTAMPZA ER in combination with other abused drugs. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. XTAMPZA ER, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of XTAMPZA ER Abuse of XTAMPZA ER poses a risk of overdose and death. The risk is increased with concurrent use of XTAMPZA ER with alcohol and/or other CNS depressants [ see Warnings and Precautions (5.1 , 5.3) , Drug Interactions (7) ] . XTAMPZA ER is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Abuse Deterrence Studies XTAMPZA ER capsules contain microspheres formulated with inactive ingredients intended to make the formulation more difficult to manipulate for misuse and abuse. In Vitro Testing In vitro physical and chemical manipulation studies were performed to evaluate the success of different methods of defeating the extended-release formulation. Results support that, relative to immediate-release oxycodone tablets, XTAMPZA ER is less susceptible to the effects of grinding, crushing, and extraction using a variety of tools and solvents. XTAMPZA ER resisted attempts to pass the melted capsule contents or the microspheres suspended in water through a hypodermic needle. Pharmacokinetic Studies The pharmacokinetic profile of manipulated XTAMPZA ER capsule contents (36 mg; [equivalent to 40 mg oxycodone HCl]) was characterized following oral (three studies) and intranasal (two studies) administration. The studies were conducted in a randomized, cross-over design. In studies assessing manipulation by crushing, the most effective crushing method identified in previous in vitro studies was applied to the product(s). Oral Pharmacokinetic Studies, Manipulated and Intact XTAMPZA ER The effect of two types of product manipulation (crushing and chewing) on XTAMPZA ER pharmacokinetics was measured in three studies. In one oral pharmacokinetic study, XTAMPZA ER capsule contents were crushed or chewed prior to oral administration in healthy, naltrexone-blocked volunteers. The two comparators in this study were intact XTAMPZA ER capsules and an immediate-release solution of oxycodone at an equivalent dose. In two oral pharmacokinetic studies, XTAMPZA ER capsule contents were crushed prior to oral administration in healthy, naltrexone-blocked volunteers. The comparators in these studies included intact XTAMPZA ER capsules, intact and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets at an equivalent dose, and crushed immediate-release oxycodone tablets at an equivalent dose. The data displayed in Table 3 illustrate the findings from the oral pharmacokinetic studies (data were similar for the two oral pharmacokinetic studies comparing XTAMPZA ER to OXYCONTIN). Collectively, the data demonstrated that crushing or chewing XTAMPZA ER prior to administration did not increase the maximum observed plasma concentration (C max ) or total exposure (AUC 0-INF ) relative to dosing the intact product under fed conditions. Relative to immediate-release oxycodone and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets, the C max for all XTAMPZA ER treatments was lower and the T max longer, consistent with an extended-release profile. Table 3: Oxycodone Pharmacokinetic Parameters, Administration of Manipulated and Intact Dosage Forms (36 mg of XTAMPZA ER or equivalent) C max (ng/mL) T max (hr) AUC 0-INF (hr∙ng/mL) Values shown for C max and AUC 0-INF are mean (standard deviation); values shown for T max are median (minimum-maximum). Treatment Oral Pharmacokinetic Study 1 Intact XTAMPZA ER Capsules (fed) 62.3 (13.0) 4.0 (1.5-6) 561 (124) Crushed XTAMPZA ER Capsule Contents (fed) 57.6 (12.6) 4.5 (2.5-6) 553 (134) Chewed XTAMPZA ER Capsule Contents (fed) 55.6 (10.9) 4.5 (2.5-8) 559 (113) Immediate-Release Oxycodone Solution (fasted) 115 (27.3) 0.75 (0.5-2) 489 (80.2) Oral Pharmacokinetic Study 2 Intact XTAMPZA ER Capsules (fed) 67.5 (17.6) 3.5 (1.25-6.0) 581 (138) Crushed XTAMPZA ER Capsule Contents (fed) 62.9 (12.6) 4.0 (2.0-7.0) 597 (149) Intact reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) 64.9 (13.8) 5.0 (2.0-10.0) 611 (145) Crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) 78.4 (12.9) 1.75 (0.5-5.0) 587 (132) Crushed Immediate-Release Oxycodone Tablets (fed) 79.4 (17.1) 1.75 (0.5-4.0) 561 (146) Nasal Pharmacokinetic Studies The pharmacokinetic profile following intranasal administration of crushed XTAMPZA ER capsule contents was characterized in two clinical studies. In Nasal Pharmacokinetic Study 1, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent, naltrexone-blocked subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and oxycodone HCl powder (intranasal) at an equivalent dose. In Nasal Pharmacokinetic Study 2, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and crushed oxycodone immediate-release tablets (intranasal) at an equivalent dose. The results of Nasal Pharmacokinetic Studies 1 and 2 are comparable and both studies demonstrated that intranasal administration of crushed XTAMPZA ER capsule contents did not result in higher peak plasma concentration (C max ) or shorter time to peak concentration (T max ) than taking XTAMPZA ER orally. The data from Nasal Pharmacokinetic Study 2 are displayed in Table 4 to represent these findings. Table 4: Oxycodone Pharmacokinetic Parameters, Nasal Pharmacokinetic Study 2: Treatment C max (ng/mL) T max (hr) AUC 0-INF (hr∙ng/mL) Values shown for C max and AUC 0-INF are mean (standard deviation); values shown for T max are median (minimum-maximum). Intact XTAMPZA ER Capsules (oral) 41.0 (10.0) 5.1 (1.6-8.1) 477 (89.6) Crushed XTAMPZA ER Capsule Contents (nasal) 29.8 (6.6) 5.1 (1.6-12.1) 459 (106) Crushed Immediate-Release Tablets (nasal) 60.9 (11.9) 2.6 (0.3-6.1) 577 (124) Clinical Studies Oral Abuse Potential Studies: The oral abuse potential of chewed XTAMPZA ER was evaluated in two studies. In a randomized, double-blind, active- and placebo-controlled, single-dose, six-way crossover pharmacodynamic study, 52 non-dependent recreational opioid users received orally-administered active and placebo treatment. The six treatment arms were intact XTAMPZA ER (36 mg, fed and fasted); chewed XTAMPZA ER (36 mg, fed and fasted); crushed immediate-release (IR) oxycodone HCl in solution (40 mg, fasted, equivalent to 36 mg of XTAMPZA ER), and placebo. Data for chewed and intact XTAMPZA ER and crushed IR oxycodone in the fasted state are described below. Drug Liking was measured on a bipolar 100-point Visual Analog Scale (VAS) where 50 represents a neutral response, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar 100-point VAS where 50 represents a neutral response, 0 represents the strongest negative response (e.g., 'definitely would not take drug again'), and 100 represents the strongest positive response (e.g., 'definitely would take drug again'). Fifty-two subjects completed the study, and the results are summarized in Table 5. The oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking and Take Drug Again VAS scores compared with crushed immediate-release oxycodone. In addition, the Drug Liking and Take Drug Again scores were similar for XTAMPZA ER taken in the intact and chewed states. Table 5: Summary of Maximum Drug Liking and Take Drug Again (E max ) Following Oral Administration XTAMPZA ER Intact (Fasted) XTAMPZA ER Chewed (Fasted) Crushed IR Oxycodone (Fasted) Placebo Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) (E max ) Mean (SD) 73.9 (15.10) 73.3 (14.93) 86.40 (12.01) 55.8 (9.94) Median (Range) 73.5 (50-100) 73.5 (50-100) 88.5 (52-100) 50.0 (50-86) Take Drug Again (E max ) Mean (SD) 77.98 (21.07) 77.85 (18.30) 87.69 (12.90) 50.79 (21.41) Median (Range) 80.5 (1-100) 81.5 (50-100) 90.5 (50-100) 50.0 (0-100) A prior, similarly-designed study was also conducted to evaluate the oral abuse potential of chewed XTAMPZA ER. Although the oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking scores compared with crushed immediate-release oxycodone, the results for Take Drug Again showed small differences that were not statistically significant. Nasal Abuse Potential Study: In a randomized, double-blind, active- and placebo-controlled, single-dose, four-way crossover pharmacodynamic study, 39 recreational opioid users with a history of intranasal drug abuse received nasally administered active and placebo drug treatment. The four treatment arms were crushed XTAMPZA ER 36 mg dosed intranasally; intact XTAMPZA ER 36 mg dosed orally; crushed immediate-release oxycodone HCl 40 mg (equivalent to 36 mg of XTAMPZA ER) dosed intranasally; and placebo. Data for intranasal XTAMPZA ER and crushed immediate-release oxycodone are described below. Thirty-six subjects completed the study. Intranasal administration of crushed XTAMPZA ER was associated with statistically lower mean Drug Liking and Take Drug Again scores compared with crushed immediate-release oxycodone (summarized in Table 6). Table 6: Summary of Maximum Drug Liking and Take Drug Again (E max ) Following Intranasal Administration XTAMPZA ER Intranasal Crushed IR Oxycodone Intranasal Placebo E max = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. Drug Liking Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response). (E max ) Mean (SD) 61.81 (15.64) 82.72 (10.95) 54.5 (11.77) Median (Range) 59.5 (16-94) 84 (60-100) 51 (28-93) Take Drug Again (E max ) Mean (SD) 47.67 (27.84) 71.36 (23.49) 45.92 (17.50) Median (Range) 50 (0-100) 78.5 (18-100) 50 (0-97) Figure 1 demonstrates a comparison of Drug Liking for intranasal administration of crushed XTAMPZA ER compared to crushed immediate-release oxycodone in subjects who received both treatments (N=36). The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for XTAMPZA ER vs. immediate-release oxycodone greater than or equal to the value on the X-axis. Approximately 92% (n = 33) of subjects had some reduction in drug liking with XTAMPZA ER relative to crushed immediate-release oxycodone HCl. Approximately 78% (n = 28) of subjects had a reduction of at least 30% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl, and approximately 58% (n = 21) of subjects had a reduction of at least 50% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl. Figure 1: Percent Reduction Profiles for E max of Drug Liking VAS for Crushed XTAMPZA ER vs. Crushed Immediate-release Oxycodone, N=36 Following Intranasal Administration Figure 1 Summary The in vitro data demonstrate that XTAMPZA ER has physicochemical properties expected to make abuse by injection difficult. The data from pharmacokinetic and human abuse potential studies, along with support from the in vitro data, also indicate that XTAMPZA ER has physicochemical properties that are expected to reduce abuse via the oral and intranasal routes. The data from the oral pharmacokinetic studies of crushed or chewed XTAMPZA ER demonstrated a lack of dose dumping with no increase in oxycodone levels compared to intact XTAMPZA ER. However, abuse of XTAMPZA ER by injection and by the oral and nasal routes of administration is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of XTAMPZA ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. XTAMPZA ER contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.3) ] . 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not abruptly discontinue XTAMPZA ER in a patient physically dependent on opioids. Rapid tapering of XTAMPZA ER in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing XTAMPZA ER, gradually taper the dosage using a patient-specific plan that considers the following: the dose of XTAMPZA ER the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [ see Dosage and Administration (2.6) , Warnings and Precautions (5.14) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [ see Use in Specific Populations (8.1) ].
| Cmax (ng/mL) | Tmax (hr) | AUC0-INF (hr∙ng/mL) | |
|---|---|---|---|
| Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum). | |||
| Intact XTAMPZA ER Capsules (fed) | 62.3 (13.0) | 4.0 (1.5-6) | 561 (124) |
| Crushed XTAMPZA ER Capsule Contents (fed) | 57.6 (12.6) | 4.5 (2.5-6) | 553 (134) |
| Chewed XTAMPZA ER Capsule Contents (fed) | 55.6 (10.9) | 4.5 (2.5-8) | 559 (113) |
| Immediate-Release Oxycodone Solution (fasted) | 115 (27.3) | 0.75 (0.5-2) | 489 (80.2) |
| Intact XTAMPZA ER Capsules (fed) | 67.5 (17.6) | 3.5 (1.25-6.0) | 581 (138) |
| Crushed XTAMPZA ER Capsule Contents (fed) | 62.9 (12.6) | 4.0 (2.0-7.0) | 597 (149) |
| Intact reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) | 64.9 (13.8) | 5.0 (2.0-10.0) | 611 (145) |
| Crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed) | 78.4 (12.9) | 1.75 (0.5-5.0) | 587 (132) |
| Crushed Immediate-Release Oxycodone Tablets (fed) | 79.4 (17.1) | 1.75 (0.5-4.0) | 561 (146) |
| Treatment | Cmax (ng/mL) | Tmax (hr) | AUC0-INF (hr∙ng/mL) |
|---|---|---|---|
| Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum). | |||
| Intact XTAMPZA ER Capsules (oral) | 41.0 (10.0) | 5.1 (1.6-8.1) | 477 (89.6) |
| Crushed XTAMPZA ER Capsule Contents (nasal) | 29.8 (6.6) | 5.1 (1.6-12.1) | 459 (106) |
| Crushed Immediate-Release Tablets (nasal) | 60.9 (11.9) | 2.6 (0.3-6.1) | 577 (124) |
| XTAMPZA ER Intact (Fasted) | XTAMPZA ER Chewed (Fasted) | Crushed IR Oxycodone (Fasted) | Placebo | ||
|---|---|---|---|---|---|
| Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. | |||||
| Drug Liking | Mean (SD) | 73.9 (15.10) | 73.3 (14.93) | 86.40 (12.01) | 55.8 (9.94) |
| Median (Range) | 73.5 (50-100) | 73.5 (50-100) | 88.5 (52-100) | 50.0 (50-86) | |
| Take Drug Again (Emax) | Mean (SD) | 77.98 (21.07) | 77.85 (18.30) | 87.69 (12.90) | 50.79 (21.41) |
| Median (Range) | 80.5 (1-100) | 81.5 (50-100) | 90.5 (50-100) | 50.0 (0-100) | |
| XTAMPZA ER Intranasal | Crushed IR Oxycodone Intranasal | Placebo | ||
|---|---|---|---|---|
| Emax = maximum (peak) effect; ER = extended-release; IR = immediate-release; VAS = visual analogue scale; SD=Standard Deviation. | ||||
| Drug Liking | Mean (SD) | 61.81 (15.64) | 82.72 (10.95) | 54.5 (11.77) |
| Median (Range) | 59.5 (16-94) | 84 (60-100) | 51 (28-93) | |
| Take Drug Again | Mean (SD) | 47.67 (27.84) | 71.36 (23.49) | 45.92 (17.50) |
| Median (Range) | 50 (0-100) | 78.5 (18-100) | 50 (0-97) | |
Overdosage of XTAMPZA ER
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Clinical Presentation Acute overdosage with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology (12.2) ] . Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid antagonist. Because the duration of reversal would be expected to be less than the duration of action of oxycodone in XTAMPZA ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. XTAMPZA ER will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or only brief in nature, administer additional antagonist as directed in the product's prescribing information. In an individual physically dependent on opioids, administration of the usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7) ] Adrenal Insufficiency [see Warnings and Precautions (5.9) ] Severe Hypotension [see Warnings and Precautions (5.10) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12) ] Seizures [see Warnings and Precautions (5.13) ] Withdrawal [see Warnings and Precautions (5.14) ] Most common adverse reactions (>5%) were nausea, headache, constipation, somnolence, pruritus, vomiting, and dizziness. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Collegium Pharmaceutical, Inc. at 1-855-331-5615 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of XTAMPZA ER was evaluated in a Phase 3, randomized-withdrawal, double-blind clinical trial involving 740 patients with moderate-to-severe chronic lower back pain. In the double-blind maintenance phase, 389 patients were randomized and 193 patients were assigned to the XTAMPZA ER treatment group. The most common AEs (>5%) reported by patients in the Phase 3 clinical trial during the titration phase were: nausea (16.6%), headache (13.9%), constipation (13.0%), somnolence (8.8%), pruritus (7.4%), vomiting (6.4%), and dizziness (5.7%). The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing XTAMPZA ER with placebo are shown in Table 1 below: Table 1: Common Adverse Reactions (>5%) Titration Maintenance Adverse Reaction XTAMPZA ER (n = 740) (%) XTAMPZA ER (n = 193) (%) Placebo (n = 196) (%) Nausea 16.6 10.9 4.6 Headache 13.9 6.2 11.7 Constipation 13.0 5.2 0.5 Somnolence 8.8 <1 <1 Pruritus 7.4 2.6 1.5 Vomiting 6.4 4.1 1.5 Dizziness 5.7 1.6 0 In the Phase 3 clinical trial, the following adverse reactions were reported in patients treated with XTAMPZA ER with incidences of 1% to 5%: Eye disorders : vision blurred Gastrointestinal disorders : abdominal pain, upper abdominal pain, diarrhea, gastroesophageal reflux disease General disorders and administration site conditions : chills, drug withdrawal syndrome, fatigue, irritability, edema, pyrexia Injury, poisoning and procedural complications : excoriation Metabolism and nutrition disorders : decreased appetite, hyperglycemia Musculoskeletal and connective tissue disorders : arthralgia, back pain, musculoskeletal pain, myalgia Nervous system disorders : migraine, tremor Psychiatric disorders : anxiety, insomnia, withdrawal syndrome Respiratory, thoracic and mediastinal disorders : cough, oropharyngeal pain Skin and subcutaneous tissue disorders : hyperhidrosis, rash Vascular disorders : hot flush, hypertension In the Phase 3 clinical trial, the following treatment-related adverse reactions were reported in patients treated with XTAMPZA ER with incidences of less than 1% of patients. Investigations : increased gamma-glutamyl transferase, increased heart rate Nervous system disorders : lethargy, memory impairment, poor-quality sleep Psychiatric disorders : abnormal dreams, euphoric mood, restlessness Respiratory, thoracic and mediastinal disorders : dyspnea Skin and subcutaneous tissue disorders : night sweats 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in XTAMPZA ER. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2) ] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7) ] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids . Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).
| Titration | Maintenance | ||
|---|---|---|---|
| Adverse Reaction | XTAMPZA ER (n = 740) (%) | XTAMPZA ER (n = 193) (%) | Placebo (n = 196) (%) |
| Nausea | 16.6 | 10.9 | 4.6 |
| Headache | 13.9 | 6.2 | 11.7 |
| Constipation | 13.0 | 5.2 | 0.5 |
| Somnolence | 8.8 | <1 | <1 |
| Pruritus | 7.4 | 2.6 | 1.5 |
| Vomiting | 6.4 | 4.1 | 1.5 |
| Dizziness | 5.7 | 1.6 | 0 |
XTAMPZA ER Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.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. ( 5.3 , 7 ) Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue XTAMPZA ER if serotonin syndrome is suspected. ( 7 ) 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. ( 7 ) 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. ( 7 )
| Inhibitors of CYP3A4 and CYP2D6 | |
|---|---|
| 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 | |
| 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. | |
| Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) | |
| The concomitant use of XTAMPZA ER and CYP3A4 inducers can decrease the plasma concentration of oxycodone | |
| If concomitant use is necessary, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved | |
| Rifampin, carbamazepine, phenytoin | |
| 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 | |
| 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 | |
| Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol | |
| The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome | |
| If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue XTAMPZA ER if serotonin syndrome is suspected. | |
| 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) | |
| MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) | |
| The use of XTAMPZA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. | |
| phenelzine, tranylcypromine, linezolid | |
| May reduce the analgesic effect of XTAMPZA ER and/or precipitate withdrawal symptoms. | |
| Avoid concomitant use. | |
| Butorphanol, nalbuphine, pentazocine, buprenorphine | |
| Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. | |
| 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 [ | |
| Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. | |
| Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. | |
| The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. | |
| Evaluate patients for signs of urinary retention or reduced gastric motility when XTAMPZA ER is used concomitantly with anticholinergic drugs. | |
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. In addition, when oxycodone binds to mu-opioid receptors, it results in positive subjective effects, such as drug liking, euphoria, and high. 12.2 Pharmacodynamics Effects on the Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in CO 2 tension and to electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations [see Overdosage (10) ] . Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships Studies in normal volunteers and patients reveal predictable relationships between oxycodone dosage and plasma oxycodone concentrations, as well as between concentration and certain expected opioid effects, such as pupillary constriction, sedation, overall subjective "drug effect," analgesia, and feelings of relaxation. The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.5) ] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions. 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 max is lower, but AUC is similar. Compared to immediate-release oxycodone solution dosed under fasted conditions the mean C max of 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 max of 100-150% and AUC of 50-60% compared to the fasted state. Following a medium-fat medium-calorie meal, the C max increased by 84% and AUC by 28% compared to the fasted state. Following a low-fat low-calorie meal, C max was 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 max and AUC 0-INF are mean (standard deviation); values shown for T max are 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 ½ for 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 ½ for 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 max by 170% and 100%, respectively [see Drug Interactions (7) ] . CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and C max values by 86% and 63%, respectively [see Drug Interactions (7) ] . CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via CYP2D6. While this pathway may be blocked by a variety of drugs such as certain cardiovascular drugs (e.g., quinidine) and antidepressants (e.g., fluoxetine), such blockade is not expected to be of clinical significance for XTAMPZA ER [see Drug Interactions (7) ] .
| Treatment | Cmax (ng/mL) | Tmax (hr) | AUC0-INF (hr∙ng/mL) |
|---|---|---|---|
| Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are 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) |
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. In addition, when oxycodone binds to mu-opioid receptors, it results in positive subjective effects, such as drug liking, euphoria, and high.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Effects on the Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in CO 2 tension and to electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations [see Overdosage (10) ] . Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships Studies in normal volunteers and patients reveal predictable relationships between oxycodone dosage and plasma oxycodone concentrations, as well as between concentration and certain expected opioid effects, such as pupillary constriction, sedation, overall subjective "drug effect," analgesia, and feelings of relaxation. The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.5) ] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.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 max is lower, but AUC is similar. Compared to immediate-release oxycodone solution dosed under fasted conditions the mean C max of 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 max of 100-150% and AUC of 50-60% compared to the fasted state. Following a medium-fat medium-calorie meal, the C max increased by 84% and AUC by 28% compared to the fasted state. Following a low-fat low-calorie meal, C max was 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 max and AUC 0-INF are mean (standard deviation); values shown for T max are 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 ½ for 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 ½ for 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 max by 170% and 100%, respectively [see Drug Interactions (7) ] . CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and C max values by 86% and 63%, respectively [see Drug Interactions (7) ] . CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via CYP2D6. While this pathway may be blocked by a variety of drugs such as certain cardiovascular drugs (e.g., quinidine) and antidepressants (e.g., fluoxetine), such blockade is not expected to be of clinical significance for XTAMPZA ER [see Drug Interactions (7) ] .
| Treatment | Cmax (ng/mL) | Tmax (hr) | AUC0-INF (hr∙ng/mL) |
|---|---|---|---|
| Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are 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) |
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS XTAMPZA ER is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.8) ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12) ] Hypersensitivity (e.g., anaphylaxis) to oxycodone. Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Hypersensitivity to oxycodone ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION XTAMPZA ER (oxycodone) extended-release capsules are an opioid agonist for oral use. The capsules contain microspheres formulated with oxycodone base and are supplied in strengths of 9 mg (equivalent to 10 mg oxycodone HCl), 13.5 mg (equivalent to 15 mg oxycodone HCl), 18 mg (equivalent to 20 mg oxycodone HCl), 27 mg (equivalent to 30 mg oxycodone HCl), and 36 mg (equivalent to 40 mg oxycodone HCl) capsules. The capsule strengths describe the amount of oxycodone base per capsule. The structural formula for oxycodone is as follows: C 18 H 21 NO 4 MW 315.37 g/mol The chemical name is 4,5 α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one. Oxycodone base is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone is present as myristate salt in the XTAMPZA ER formulation. Each XTAMPZA ER capsule contains either 9, 13.5, 18, 27, or 36 mg of oxycodone (equivalent to 10, 15, 20, 30, or 40 mg of oxycodone HCl, respectively) and the following inactive ingredients: myristic acid, yellow beeswax, carnauba wax, stearoyl polyoxyl-32 glycerides, magnesium stearate, and colloidal silicon dioxide. The capsule shells collectively contain titanium dioxide, hypromellose, and water. Additionally, the 9 mg and 18 mg strength capsule shells contain yellow iron oxide, the 13.5 and 36 mg strength capsule shells contain red iron oxide, and the 27 mg strength capsule shells contain black iron oxide. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.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. ( 2.1 ) 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 ) 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 ) 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 , 5 ) 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 , 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 ( 2.1 , 5.2 ) 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 , 5.1 , 5.2 , 5.3 ) 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 ) 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 ) 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 , 8.6 ) 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 , 5.14 ) 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 ) 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 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. 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.
| Oxycodone Hydrochloride | Oxycodone base (XTAMPZA ER) |
|---|---|
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS 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" Extended-release capsules: 9 mg (equivalent to 10 mg oxycodone HCl) 13.5 mg (equivalent to 15 mg oxycodone HCl) 18 mg (equivalent to 20 mg oxycodone HCl) 27 mg (equivalent to 30 mg oxycodone HCl) 36 mg (equivalent to 40 mg oxycodone HCl). ( 3 )
| 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" |
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.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. ( 1 ) Limitations of Use ( 1 ) 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.
Spl product data elements
Usually a list of ingredients in a drug product.XTAMPZA ER OXYCODONE OXYCODONE OXYCODONE MYRISTIC ACID YELLOW WAX CARNAUBA WAX PEG-32 STEARATE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE WATER FERRIC OXIDE YELLOW ivory Size 3 XTAMPZA;ER;9;mg XTAMPZA ER OXYCODONE OXYCODONE OXYCODONE MYRISTIC ACID YELLOW WAX CARNAUBA WAX PEG-32 STEARATE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE WATER FERRIC OXIDE RED swedish orange Size 2 XTAMPZA;ER;13;5;mg XTAMPZA ER OXYCODONE OXYCODONE OXYCODONE MYRISTIC ACID YELLOW WAX CARNAUBA WAX PEG-32 STEARATE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE WATER FERRIC OXIDE YELLOW rich yellow Size 1 XTAMPZA;ER;18;mg XTAMPZA ER OXYCODONE OXYCODONE OXYCODONE MYRISTIC ACID YELLOW WAX CARNAUBA WAX PEG-32 STEARATE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE WATER FERROSOFERRIC OXIDE light gray Size 0 XTAMPZA;ER;27;mg XTAMPZA ER OXYCODONE OXYCODONE OXYCODONE MYRISTIC ACID YELLOW WAX CARNAUBA WAX PEG-32 STEARATE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE WATER FERRIC OXIDE RED flesh Size 00 XTAMPZA;ER;36;mg
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology The safety of beeswax, carnauba wax, and myristic acid in XTAMPZA ER in doses exceeding a total daily dose of 288 mg oxycodone per day (equivalent to 320 mg oxycodone HCl per day) has not been studied.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted. Mutagenesis Oxycodone was genotoxic in the in vitro mouse lymphoma assay. Oxycodone was negative when tested at appropriate concentrations in the in vitro chromosomal aberration assay, the in vitro bacterial reverse mutation assay (Ames test), and the in vivo bone marrow micronucleus assay in mice. Impairment of Fertility In a study of reproductive performance, rats were administered a once daily gavage dose of the vehicle or oxycodone hydrochloride (0.5, 2, and 8 mg/kg). Male rats were dosed for 28 days before cohabitation with females, during the cohabitation and until necropsy (2-3 weeks post-cohabitation). Females were dosed for 14 days before cohabitation with males, during cohabitation and up to Gestation Day 6. Oxycodone HCl did not affect reproductive function in male or female rats at any dose tested (≤8 mg/kg/day), up to 1.3 times a human dose of 60 mg/day.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted. Mutagenesis Oxycodone was genotoxic in the in vitro mouse lymphoma assay. Oxycodone was negative when tested at appropriate concentrations in the in vitro chromosomal aberration assay, the in vitro bacterial reverse mutation assay (Ames test), and the in vivo bone marrow micronucleus assay in mice. Impairment of Fertility In a study of reproductive performance, rats were administered a once daily gavage dose of the vehicle or oxycodone hydrochloride (0.5, 2, and 8 mg/kg). Male rats were dosed for 28 days before cohabitation with females, during the cohabitation and until necropsy (2-3 weeks post-cohabitation). Females were dosed for 14 days before cohabitation with males, during cohabitation and up to Gestation Day 6. Oxycodone HCl did not affect reproductive function in male or female rats at any dose tested (≤8 mg/kg/day), up to 1.3 times a human dose of 60 mg/day. 13.2 Animal Toxicology The safety of beeswax, carnauba wax, and myristic acid in XTAMPZA ER in doses exceeding a total daily dose of 288 mg oxycodone per day (equivalent to 320 mg oxycodone HCl per day) has not been studied.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 9 mg Capsule Bottle Label NDC 24510-110-10 Xtampza ® ER (oxycodone) EXTENDED-RELEASE CAPSULES CII 9 mg Each capsule contains Oxycodone 9 mg (Equivalent to 10 mg Oxycodone Hydrochloride) 100 Capsules R x Only Always take with food. Taking on an empty stomach can decrease drug absorption. Attention Dispenser: Accompanying Medication Guide must be provided to the patient upon dispensing. PRINCIPAL DISPLAY PANEL - 9 mg Capsule Bottle Label
PRINCIPAL DISPLAY PANEL - 13.5 mg Capsule Bottle Label NDC 24510-115-10 Xtampza ® ER (oxycodone) EXTENDED-RELEASE CAPSULES CII 13.5 mg Each capsule contains Oxycodone 13.5 mg (Equivalent to 15 mg Oxycodone Hydrochloride) 100 Capsules R x Only Always take with food. Taking on an empty stomach can decrease drug absorption. Attention Dispenser: Accompanying Medication Guide must be provided to the patient upon dispensing. PRINCIPAL DISPLAY PANEL - 13.5 mg Capsule Bottle Label
PRINCIPAL DISPLAY PANEL - 18 mg Capsule Bottle Label NDC 24510-120-10 Xtampza ® ER (oxycodone) EXTENDED-RELEASE CAPSULES CII 18 mg Each capsule contains Oxycodone 18 mg (Equivalent to 20 mg Oxycodone Hydrochloride) 100 Capsules R x Only Always take with food. Taking on an empty stomach can decrease drug absorption. Attention Dispenser: Accompanying Medication Guide must be provided to the patient upon dispensing. PRINCIPAL DISPLAY PANEL - 18 mg Capsule Bottle Label
PRINCIPAL DISPLAY PANEL - 27 mg Capsule Bottle Label NDC 24510-130-10 Xtampza ® ER (oxycodone) EXTENDED-RELEASE CAPSULES CII 27 mg Each capsule contains Oxycodone 27 mg (Equivalent to 30 mg Oxycodone Hydrochloride) 100 Capsules R x Only Always take with food. Taking on an empty stomach can decrease drug absorption. Attention Dispenser: Accompanying Medication Guide must be provided to the patient upon dispensing. PRINCIPAL DISPLAY PANEL - 27 mg Capsule Bottle Label
PRINCIPAL DISPLAY PANEL - 36 mg Capsule Bottle Label NDC 24510-140-10 Xtampza ® ER (oxycodone) EXTENDED-RELEASE CAPSULES CII 36 mg Each capsule contains Oxycodone 36 mg (Equivalent to 40 mg Oxycodone Hydrochloride) 100 Capsules R x Only Always take with food. Taking on an empty stomach can decrease drug absorption. Attention Dispenser: Accompanying Medication Guide must be provided to the patient upon dispensing. PRINCIPAL DISPLAY PANEL - 36 mg Capsule Bottle Label
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Boxed Warning 12/2023 Indications and Usage ( 1 ) 12/2023 Dosage and Administration ( 2.1 , 2.3 , 2.5 ) 12/2023 Warnings and Precautions ( 5.7 ) 12/2023
| 12/2023 | |
| Indications and Usage ( | 12/2023 |
| Dosage and Administration ( | 12/2023 |
| Warnings and Precautions ( | 12/2023 |
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.Healthcare professionals can telephone Collegium Pharmaceutical's Medical Affairs Department (1-855-331-5615) for information on this product. Manufactured by: Patheon Pharmaceuticals, Cincinnati, OH 45237 U.S. Patent Nos. 7,399,488; 7,771,707; 8,449,909; 8,557,291; 8,758,813; 8,840,928; 9,044,398; 9,248,195; 9,592,200; 9,682,075; 9,737,530; 9,763,883; 9,968,598; 10,004,729; 10,188,644; 10,525,052; 10,525,053; 10,646,485; and 10,668,060
XTAMPZA ER: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store XTAMPZA ER securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving XTAMPZA ER unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1 , 5.2) , Drug Abuse and Dependence (9.2) ]. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused XTAMPZA ER should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of XTAMPZA ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1) ] . Instruct patients not to share XTAMPZA ER with others and to take steps to protect XTAMPZA ER from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression including information that the risk is greatest when starting XTAMPZA ER or when the dosage is increased, and that it can occur even at recommended dosages. 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 [see Warnings and Precautions (5.2) ] . Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2) ]. Interactions with Benzodiazepines and other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if XTAMPZA ER is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [ see Warnings and Precautions (5.3) , Drug Interactions (7) ] . Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, 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) [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in cases of known or suspected opioid overdose, even if naloxone is administered [ see Overdosage (10) ]. If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone in the event of an opioid overdose To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7) , Adverse Reactions (6.2) ]. Serotonin Syndrome Inform patients that XTAMPZA ER could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7) ] . MAOI Interaction Inform patients to avoid taking XTAMPZA ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking XTAMPZA ER [see Drug Interactions (7) ] . Food Effect Because food has an effect on absorption of oxycodone from XTAMPZA ER, each dose of XTAMPZA ER should be taken with food in order to ensure that appropriate plasma levels are consistently achieved. Instruct patients to take XTAMPZA ER with approximately the same amount of food regardless of whether they swallow the capsule whole or sprinkle on soft food or into a cup and then administer directly into the mouth. XTAMPZA ER may be taken as intact capsules or, alternately, may be administered as a sprinkle on soft foods or sprinkled into a cup and administered directly into the mouth, or through a nasogastric or gastric feeding tube [see Dosage and Administration (2.1 , 2.7) ] . Important Administration Instructions [see Dosage and Administration (2.1 , 2.6 , 2.7) , Warnings and Precautions (5.2) ] Instruct patients how to properly take XTAMPZA ER, including the following: Taking XTAMPZA ER with food Swallowing XTAMPZA ER capsules whole or sprinkling the capsule contents on soft food or into a cup and administering directly into the mouth Using XTAMPZA ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue XTAMPZA ER without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.6) ] Driving or Operating Heavy Machinery Inform patients that XTAMPZA ER may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [ see Warnings and Precautions (5.15) ] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention. Adrenal Insufficiency Inform patients that XTAMPZA ER could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9) ] . Hypotension Inform patients that XTAMPZA ER may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.10) ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in XTAMPZA ER. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4) , Adverse Reactions (6) ] . Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of XTAMPZA ER for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ] . Embryofetal Toxicity Advise females of reproductive potential that XTAMPZA ER can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise patients that breastfeeding is not recommended during treatment with XTAMPZA ER [see Use in Specific Populations (8.2) ]. Infertility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) ].
Instructions for use
Information about safe handling and use of the drug product.Instructions for Use XTAMPZA ® ER (ex tamp' zah ee ar) (oxycodone) extended-release capsules, CII Always take XTAMPZA ER with approximately the same amount of food. If you cannot swallow XTAMPZA ER capsules, tell your healthcare provider. If your healthcare provider tells you that you can take XTAMPZA ER by sprinkling the capsule contents, follow these steps: XTAMPZA ER can be opened and the contents inside the capsule can be sprinkled onto soft foods (such as, applesauce, pudding, yogurt, ice cream, or jam) as follows: Figure 1 Open the XTAMPZA ER capsule and sprinkle the contents over about one tablespoon of the soft food listed above (See Figure 1 ). Figure 2 Swallow all of the soft food and sprinkled capsule contents right away. Do not save any of the soft food and capsule contents for another dose (See Figure 2 ). Figure 3 Rinse your mouth to make sure you have swallowed all of the capsule contents. (See Figure 3 ). Figure 4 Flush the empty capsule down the toilet right away (See Figure 4 ). XTAMPZA ER capsule contents can also be sprinkled into a cup and then put directly into the mouth. Giving XTAMPZA ER through a nasogastric or gastrostomy tube: Use water, milk, or a liquid nutritional supplement to flush the tube when giving XTAMPZA ER. Step 1: Flush the nasogastric or gastrostomy tube with liquid. Step 2: Open an XTAMPZA ER capsule and carefully pour the contents of the capsule directly into the tube. Do not pre-mix the capsule contents with the liquid used to flush the capsule contents through the tube. Step 3: Draw up 15 mL of liquid into a syringe, insert the syringe into the tube, and flush the contents of the capsule through the tube to give the dose. Step 4 : Flush the tube two more times, each time with 10 mL of liquid, to ensure that none of the contents of the capsule are left in the tube. This Instruction for Use has been approved by the U.S. Food and Drug Administration. Issued: DECEMBER 2023 Collegium ® PHARMACEUTICAL Figure 1 Figure 2 Figure 3 Figure 4
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| Flush the nasogastric or gastrostomy tube with liquid. | |
| Open an XTAMPZA ER capsule and carefully pour the contents of the capsule directly into the tube. | |
| Draw up 15 mL of liquid into a syringe, insert the syringe into the tube, and flush the contents of the capsule through the tube to give the dose. | |
| Flush the tube two more times, each time with 10 mL of liquid, to ensure that none of the contents of the capsule are left in the tube. |
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.Medication Guide XTAMPZA ® ER (ex tamp' zah ee ar) (oxycodone) extended-release capsules, CII This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: DECEMBER 2023 XTAMPZA ER is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage severe and persistent pain that requires an extended treatment period with a daily opioid medicine, when other pain medicines do not treat your pain well enough or you cannot tolerate them. A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed by your healthcare provider, you are at risk for opioid addiction, abuse, and misuse that can lead to death. Not to be taken on an "as needed" basis Important information about XTAMPZA ER: Get emergency help or call 911 right away if you take too much XTAMPZA ER (overdose). When you first start taking XTAMPZA ER, when your dose is changed, or if you take too much (overdose), serious life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an overdose. Taking XTAMPZA ER with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your XTAMPZA ER. They could die from taking it. Selling or giving away XTAMPZA ER is against the law. Store XTAMPZA ER securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take XTAMPZA ER if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. Before taking XTAMPZA ER, tell your healthcare provider if you have a history of: head injury, seizures problems urinating liver, kidney, thyroid problems pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take XTAMPZA ER, do not take more of XTAMPZA ER without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking XTAMPZA ER. pregnant or planning to become pregnant. Use of XTAMPZA ER for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. Not recommended during treatment with XTAMPZA ER. It may harm your baby. living in a household where there are small children or someone who has abused street or prescription drugs taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking XTAMPZA ER with certain other medicines can cause serious side effects that could lead to death. When taking XTAMPZA ER: Do not change your dose. Take XTAMPZA ER exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Take your prescribed dose every 12 hours, at the same time every day. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. If you cannot swallow XTAMPZA ER capsules, see the detailed Instructions for Use . Always take XTAMPZA ER capsules with approximately the same amount of food to ensure enough medicine is absorbed. Swallow XTAMPZA ER whole. Do not snort or inject XTAMPZA ER because this may cause you to overdose and die. The contents of the XTAMPZA ER capsules may be sprinkled on soft food, sprinkled into a cup and then put directly into the mouth, or given through a nasogastric or gastrostomy tube. Call your healthcare provider if the dose you are taking does not control your pain. Do not stop taking XTAMPZA ER without talking to your healthcare provider. Dispose of expired, unwanted, or unused XTAMPZA ER by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking XTAMPZA ER DO NOT: Drive or operate heavy machinery, until you know how XTAMPZA ER affects you. XTAMPZA ER can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with XTAMPZA ER may cause you to overdose and die. The possible side effects of XTAMPZA ER are: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of XTAMPZA ER. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. For more information, go to dailymed.nlm.nih.gov Manufactured by: Patheon Pharmaceuticals, 2110 Galbraith Road, Cincinnati, OH 45237, www.collegiumpharma.com or call 855-331-5615
| Medication Guide XTAMPZA® ER (ex tamp' zah ee ar) (oxycodone) extended-release capsules, CII | ||
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES An enriched-enrollment, randomized-withdrawal, double-blind, placebo-controlled, parallel group, study was conducted in 740 patients with persistent, moderate-to-severe chronic lower back pain, with inadequate pain control from their prior therapy. During screening, patients stopped their prior opioid analgesics and/or non-opioid analgesics prior to starting XTAMPZA ER treatment. Patients were titrated to a stable and tolerated dose between 18 mg (equivalent to 20 mg oxycodone HCl) twice daily and 72 mg (equivalent to 80 mg oxycodone HCl) twice daily of XTAMPZA ER in an open-label fashion during the first six weeks of the trial. Optional use of rescue medication (acetaminophen 500 mg tablets) up to 2 tablets every 4-6 hours was permitted during the dose titration phase, up to 2000 mg per day. XTAMPZA ER was titrated once every three to seven days until a stable and tolerable dose was identified (maximum dose of 72 mg [equivalent to 80 mg oxycodone HCl] twice daily). Following the titration phase, 389 subjects (53%) met the study randomization criteria of adequate analgesia (pain reduction of at least 2 points from screening baseline to a score of 4 or less on a 0-10 numerical rating scale) and acceptable tolerability of XTAMPZA ER and entered the randomized, double-blind maintenance phase. Subjects discontinued from the dose-titration phase for the following reasons: failure to meet entrance criteria (18%), adverse events (13%), subject request (7%) and lack of efficacy (5%). Patients were randomized at a ratio of 1:1 into a 12-week double-blind maintenance phase with their fixed stable dose of XTAMPZA ER (or matching placebo). Patients randomized to placebo were given a blinded taper of XTAMPZA ER according to a prespecified tapering schedule; XTAMPZA ER was decreased by 25% to 35% every 5 days for the higher doses of XTAMPZA ER and up to 50% every 5 days for the mid-to-lower doses of XTAMPZA ER over the first 20 days of the double-blind maintenance phase. Patients were allowed to use rescue medication (acetaminophen 500 mg tablets) up to a maximum dose of 2000 mg per day. During the double-blind maintenance phase, 122 patients (63%) completed the 12-week treatment with XTAMPZA ER and 100 (51%) completed with placebo. Overall, 11% of patients discontinued due to lack of efficacy (4% of XTAMPZA ER patients and 17% of placebo patients), and 7% discontinued due to adverse events (7% of XTAMPZA ER patients and 7% of placebo patients). In this study, there was a significant difference in pain reduction, favoring XTAMPZA ER, between XTAMPZA ER (doses of 36-144 mg per day, equivalent to 40-160 mg of oxycodone HCl) and placebo, based on the primary endpoint of change in average pain intensity from randomization baseline to Week 12 of the double-blind maintenance phase. The proportion of patients (responders) in each group who demonstrated improvement in their weekly average pain scores from screening baseline to Week 12, is shown in Figure 2. The figure is cumulative, so that patients whose change from screening is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not complete the study were classified as non-responders. Treatment with XTAMPZA ER resulted in a higher proportion of responders, defined as patients with at least a 30% and 50% improvement as compared to placebo. Figure 2: Responder Analysis for Pain Intensity: Percent Reduction/Improvement (Intent-to-Treat Population) Figure 2
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3) ] . Of the total number of subjects entered into the titration phase of the Phase 3 study for XTAMPZA ER (740), 88 (12%) were age 65 and older. In this clinical trial with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received XTAMPZA ER. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. Use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease, and use of other drug therapy. Respiratory depression is the chief risk in elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of XTAMPZA ER slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.8) ] .
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness of XTAMPZA ER in pediatric patients below the age of 18 years have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)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/m 2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no 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/m 2 basis). However, body weight of these pups recovered. In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human oral dose of 60 mg/day on a mg/m 2 basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/m 2 basis).
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Not recommended. ( 8.2 ) 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/m 2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no 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/m 2 basis). However, body weight of these pups recovered. In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human oral dose of 60 mg/day on a mg/m 2 basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/m 2 basis). 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. 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) , Clinical Pharmacology (12.2) , Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use Safety and effectiveness of XTAMPZA ER in pediatric patients below the age of 18 years have not been established. 8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3) ] . Of the total number of subjects entered into the titration phase of the Phase 3 study for XTAMPZA ER (740), 88 (12%) were age 65 and older. In this clinical trial with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received XTAMPZA ER. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. Use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease, and use of other drug therapy. Respiratory depression is the chief risk in elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of XTAMPZA ER slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.8) ] . 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) ] . 8.7 Renal Impairment In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Follow a conservative approach to dose initiation and adjust according to the clinical situation. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg [see Clinical Pharmacology (12.3) ] . 8.8 Sex Differences In pharmacokinetic studies with XTAMPZA ER, healthy female subjects demonstrate up to 20% higher oxycodone plasma exposures than males, even after considering differences in body weight or BMI. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages. In the Phase 3 clinical trial there was a greater frequency of typical opioid adverse events for females than males; there was no male/female difference detected for efficacy.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING XTAMPZA ER capsules are supplied in 100-count bottles with a child-resistant closure and as a hospital unit dose package with 10 individually blistered capsules per card; two cards per carton as follows: Table 8: Summary of XTAMPZA ER Capsule Strengths and Packaging Configurations Strength Capsule Description NDC Number (100-count Bottles with a child-resistant closure) NDC Number (20-count Hospital Unit Dose Blister Cartons) 9 mg (equivalent to 10 mg oxycodone HCl) Size 3, ivory cap printed with "XTAMPZA ER" and white body printed with "9 mg" NDC 24510-110-10 NDC 24510-110-20 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" NDC 24510-115-10 NDC 24510-115-20 18 mg (equivalent to 20 mg oxycodone HCl) Size 1, rich yellow cap printed with "XTAMPZA ER" and white body printed with "18 mg" NDC 24510-120-10 NDC 24510-120-20 27 mg (equivalent to 30 mg oxycodone HCl) Size 0, light gray cap printed with "XTAMPZA ER" and white body printed with "27 mg" NDC 24510-130-10 NDC 24510-130-20 36 mg (equivalent to 40 mg oxycodone HCl) Size 00, flesh color cap printed with "XTAMPZA ER" and white body printed with "36 mg" NDC 24510-140-10 NDC 24510-140-20 Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container, with child-resistant closure. Store XTAMPZA ER securely and dispose of properly [see Patient Counseling Information (17) ] .
| Strength | Capsule Description | NDC Number (100-count Bottles with a child-resistant closure) | NDC Number (20-count Hospital Unit Dose Blister Cartons) |
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| 9 mg (equivalent to 10 mg oxycodone HCl) | Size 3, ivory cap printed with "XTAMPZA ER" and white body printed with "9 mg" | NDC 24510-110-10 | NDC 24510-110-20 |
| 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" | NDC 24510-115-10 | NDC 24510-115-20 |
| 18 mg (equivalent to 20 mg oxycodone HCl) | Size 1, rich yellow cap printed with "XTAMPZA ER" and white body printed with "18 mg" | NDC 24510-120-10 | NDC 24510-120-20 |
| 27 mg (equivalent to 30 mg oxycodone HCl) | Size 0, light gray cap printed with "XTAMPZA ER" and white body printed with "27 mg" | NDC 24510-130-10 | NDC 24510-130-20 |
| 36 mg (equivalent to 40 mg oxycodone HCl) | Size 00, flesh color cap printed with "XTAMPZA ER" and white body printed with "36 mg" | NDC 24510-140-10 | NDC 24510-140-20 |
Storage and handling
Information about safe storage and handling of the drug product.Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container, with child-resistant closure. Store XTAMPZA ER securely and dispose of properly [see Patient Counseling Information (17) ] .
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.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. ( 5.1 ) 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 ) Accidental ingestion of XTAMPZA ER, especially by children, can result in fatal overdose of oxycodone. ( 5.2 ) 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 , 7 ) 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 ) 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 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone from XTAMPZA ER. ( 5.6 , 12.3 ) 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)] .
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API