Oxycodone Extended-Release Capsules

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

Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in CO2 tension and 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].

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.

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.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].

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.

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 potent agonist opioids. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION].

There is a relationship between increasing oxycodone plasma concentration and increasing frequency of doserelated opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioidtolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

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.

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

Compared to immediate-release oxycodone solution dosed under fasted conditions the mean Cmax 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 (Tmax) 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 (t½) 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 Cmax of 100-150% and AUC of 50-60% compared to the fasted state. Following a medium-fat medium-calorie meal, the Cmax increased by 84% and AUC by 28% compared to the fasted state. Following a low-fat low-calorie meal, Cmax 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)

Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum - maximum).

Following intravenous administration, the steady-state volume of distribution (Vss) 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].

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 Odemethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see DRUG INTERACTIONS].

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

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

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].

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 t½ for oxycodone of 1 hour.

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 t½ for oxycodone increased by 2.3 hours.

Drug Interaction Studies

CYP3A4 is the major enzyme involved in noroxycodone formation. Co-administration of OXYCONTIN (10 mg single dose) and the CYP3A4 inhibitor ketoconazole (200 mg BID) increased oxycodone AUC and Cmax by 170% and 100%, respectively [see DRUG INTERACTIONS].

A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively [see DRUG INTERACTIONS].

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].

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.

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 nonopioid 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)

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

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

Clinical Trial Experience

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

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

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

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

Table 1: Common Adverse Reactions ( > 5%)

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

Eye disorders: vision blurred

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

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

Injury, poisoning and procedural complications: excoriation

Metabolism and nutrition disorders: decreased appetite, hyperglycemia

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

Nervous system disorders: migraine, tremor

Psychiatric disorders: anxiety, insomnia, withdrawal syndrome

Respiratory, thoracic and mediastinal disorders: cough, oropharyngeal pain

Skin and subcutaneous tissue disorders: hyperhidrosis, rash

Vascular disorders: hot flush, hypertension

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

Investigations: increased gamma-glutamyl transferase, increased heart rate

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

Psychiatric disorders: abnormal dreams, euphoric mood, restlessness

Respiratory, thoracic and mediastinal disorders: dyspnea

Skin and subcutaneous tissue disorders: night sweats

Postmarketing Experience

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

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

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

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in XTAMPZA ER.

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

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

• It is used to ease pain.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Feeling confused.
• Very hard stools (constipation).
• Very bad belly pain.
• Feeling very tired or weak.
• Trouble breathing, slow breathing, or shallow breathing.
• Trouble passing urine.
• Fast or slow heartbeat.
• A heartbeat that does not feel normal.
• Seizures.
• Shakiness.
• Change in eyesight.
• Chest pain or pressure.
• Hallucinations (seeing or hearing things that are not there).
• Mood changes.
• Memory problems or loss.
• Trouble walking.
• Trouble speaking.
• Swelling in the arms or legs.
• Feeling very sleepy.
• Fever.
• A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take this medicine (oxycodone extended-release capsules) with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
• Taking an opioid drug like this medicine may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine (oxycodone extended-release capsules) is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Review Date: October 4, 2017