Xartemis XR

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Xartemis XR, there are no specific foods that you must exclude from your diet when receiving this medication.

Oxycodone is an opioid pain medication. An opioid is sometimes called a narcotic. Acetaminophen is a less potent pain reliever that increases the effects of oxycodone.

Acetaminophen and oxycodone is a combination medicine used to relieve moderate to severe pain.

Acetaminophen and oxycodone may also be used for purposes not listed in this medication guide.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose can be fatal, especially in a child or other person using this medicine without a prescription. Overdose symptoms may include slow breathing and heart rate, severe drowsiness, muscle weakness, cold and clammy skin, pinpoint pupils, and fainting.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness.

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.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Very bad dizziness or passing out.
• Feeling very sleepy.
• Trouble breathing, slow breathing, or shallow breathing.
• Feeling confused.
• Hallucinations (seeing or hearing things that are not there).
• Mood changes.
• Very hard stools (constipation).
• Very bad belly pain.
• Feeling very tired or weak.
• A burning, numbness, or tingling feeling that is not normal.
• Not able to pass urine or change in how much urine is passed.
• Fast or slow heartbeat.
• A heartbeat that does not feel normal.
• Fever or chills.
• Sore throat.
• Hearing loss.
• Seizures.
• Very bad headache.
• Shakiness.
• Any unexplained bruising or bleeding.
• Change in eyesight.
• Chest pain.
• Memory problems or loss.
• Trouble walking.
• Trouble speaking.
• Swelling in the arms or legs.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
• 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.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

XARTEMIS XR is indicated for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)], reserve XARTEMIS XR for use in patients for whom alternative treatment options (e.g., non-opioid analgesics):

• Have not been tolerated or are not expected to be tolerated,
• Have not provided adequate analgesia or are not expected to provide adequate analgesia.

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]

• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]

• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]

• Hepatotoxicity [see Warnings and Precautions (5.5)]

• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.6)]

• Adrenal Insufficiency [see Warnings and Precautions (5.8)]

• Severe Hypotension [see Warnings and Precautions (5.9)]

• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)]

• Seizures [see Warnings and Precautions (5.15)]

• Withdrawal [see Warnings and Precautions (5.16)]

       Clinical Trials Experience

Because clinical studies 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 clinical practice.

In safety data from two Phase 3 (one placebo-controlled, one open-label) trials where multiple doses of XARTEMIS XR were administered for up to 42 days, the most common adverse reactions (reported by ≥10% in any XARTEMIS XR dose group) were: nausea, dizziness and vomiting. The most common reasons for discontinuation due to AEs in these 2 studies (reported by ≥1% in any XARTEMIS XR dose group) were vomiting (4.8%) and nausea (4.1%); there were no reports of these adverse reactions in the placebo-treated patients.

A total of 1028 subjects in 14 clinical studies were treated with XARTEMIS XR during the clinical development program, including 892 subjects treated with 15 mg oxycodone and 650 mg acetaminophen. This dosage regimen of XARTEMIS XR was administered to 607 patients in two Phase 3 studies (one placebo-controlled and one open-label).

In a placebo-controlled post-bunionectomy acute pain trial, 329 patients were dosed with 15 mg oxycodone and 650 mg acetaminophen XARTEMIS XR or placebo orally every 12 hours, for approximately 48 hours (blinded period) [see Clinical Studies (14)]. Table 1 lists the adverse reactions reported by ≥1% of XARTEMIS XR-treated patients and more frequently in XARTEMIS XR-treated patients compared with placebo.

Table 1. Treatment‑Emergent Adverse Reactions* Reported by ≥1% of XARTEMIS XR-Treated Patients and More Frequently than Placebo in XARTEMIS XR-Treated Patients with Postoperative Bunionectomy Pain (blinded period)

    *A treatment-emergent adverse reaction refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.

Other Adverse Reactions Observed During the Premarketing Evaluation of XARTEMIS XR

The following adverse drug reactions not listed above occurred in ≥1% of XARTEMIS XR-treated patients in the pooled safety data from two Phase 3 studies (including a placebo-controlled and an open-label non-controlled safety study) where multiple‑doses of XARTEMIS XR were administered every 12 hours for up to 42 days:

Gastrointestinal disorders: dry mouth, dyspepsia, diarrhea

General disorders and administration site conditions: fatigue

Investigations: hepatic enzyme increased

Psychiatric disorders: insomnia

Respiratory, thoracic and mediastinal disorders: cough

The following adverse drug reactions occurred in <1% of XARTEMIS XR-treated patients in the pooled safety data from the two Phase 3 studies described above:

Cardiac disorders: palpitations

Eye and ear disorders: tinnitus, vision blurred

Gastrointestinal disorders: abdominal discomfort, abdominal pain, esophageal spasm

General disorders and administration site conditions: asthenia, chest discomfort, chills, contusion, fall, feeling jittery, malaise, non-cardiac chest pain, thirst

Immune system disorders: hypersensitivity

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood lactate dehydrogenase increased, blood pressure increased, gamma-glutamyltransferase increased, liver functional test abnormal

Metabolic and nutritional: decreased appetite

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal stiffness

Nervous system disorders: cognitive disorder, memory impairment, migraine, myoclonus, paraesthesia, sedation, tremor

Psychiatric disorders: anxiety, confusional state, disorientation, euphoric mood, mood altered, sleep disorder, withdrawal syndrome

Renal and urinary disorders: urine flow decreased

Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups, hypopnea, oropharyngeal pain, throat irritation

Skin and subcutaneous tissue disorders: dermatitis, ecchymosis, hyperhidrosis, urticaria

Vascular disorders: flushing, hypertension

       Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Xartemis XR. 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 [see Drug Interactions (7)].

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use [see Warnings and Precautions (5.8)].

Anaphylaxis: Anaphylactic reaction has been reported with ingredients contained in Xartemis XR [see Contraindications (4)].

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

Mechanism of Action

Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid 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 for analgesia with 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.

Acetaminophen is a non-opioid, non-salicylate analgesic, and antipyretic. The site and mechanism for the analgesic effect of acetaminophen has not been determined. The antipyretic effect of acetaminophen is accomplished through the inhibition of endogenous pyrogen action on the hypothalamic heat-regulating centers.

Pharmacodynamics

Effects on the Central Nervous System

Oxycodone produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary, and pancreatic secretions are decreased by oxycodone HCl. Oxycodone, like other opioid analgesics, produces some degree of nausea and vomiting which is caused by direct stimulation of the chemoreceptor trigger zone located in the medulla. The frequency and severity of emesis gradually diminishes with time.

Oxycodone causes a reduction in motility with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

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 (active moiety) 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, 2.4)].

Concentration-Adverse Reaction Relationships

There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.4)].

The dose of Xartemis XR must be individualized because the effective analgesic dose for some patients will be too high to be tolerated by other patients [see Dosage and Administration (2.1)].

Pharmacokinetics

XARTEMIS XR is an extended-release bilayer formulation of oxycodone and acetaminophen (immediate- and extended-release layers) which is not interchangeable with other oxycodone/acetaminophen products because of differing pharmacokinetic profiles that affect the frequency of administration. The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone.

Absorption

The oral bioavailability of oxycodone is 60 to 87%. Bioavailability (dose-normalized AUC and Cmax) of oxycodone and acetaminophen following single- and multiple-doses of XARTEMIS XR tablets is comparable to immediate-release products containing oxycodone or acetaminophen.

Oxycodone plasma concentrations from this bilayer product are detectable within 30 minutes and reach a maximum concentration (Cmax) in 3 to 4 hours after XARTEMIS XR administration. Maximum plasma concentrations of acetaminophen occur in 0.75 to 1 hour after XARTEMIS XR administration.

Steady-state plasma concentrations of oxycodone and acetaminophen are achieved within 24 hours of initiation of dosing of XARTEMIS XR (prior to the third dose of two XARTEMIS XR tablets administered every 12 hours). XARTEMIS XR produces steady-state maximum plasma concentrations of oxycodone that are greater than those following the first dose, while concentrations of acetaminophen are comparable to the first dose (Table 2).

Table 2. Mean (SD) Pharmacokinetics of XARTEMIS XR (two 7.5 mg oxycodone and 325 mg acetaminophen extended-release tablets; after a single dose and multiple doses every 12 hours for 4.5 days)

*Steady-state results on Day 5 (0-12 hours)

† Fluctuation = 100•(Cmax-Cmin)/Cavg

‡ Median reported for Tmax

NA = not applicable

Food Effect

When administered with a high- or low-fat meal, median Tmax values of oxycodone were delayed by 2 hours and 1 hour, respectively. Mean AUC values are increased by 15 to 16% and peak concentrations are 12 to 25% higher for oxycodone. Food delayed median acetaminophen Tmax by 1.5 hours. There is no change in mean acetaminophen AUC values and peak concentrations are 23 to 24% lower with food. XARTEMIS XR may be administered with or without food.

Distribution

Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Oxycodone was approximately 45% bound to plasma protein at 37°C and a pH of 7.4. Oxycodone has been found in breast milk [see Use in Specific Populations (8.2)].

Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of acetaminophen is bound to plasma protein.

Elimination

Metabolism

Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present.

The formation of oxymorphone, but not noroxycodone, is mediated by CYP2D6 and as such its formation can, in theory, be affected by other drugs [see Warnings and Precautions (5.4, 5.16)].

Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:

a)   conjugation with glucuronide;

b)   conjugation with sulfate; and

c)   oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates.

The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.

In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.

Excretion

Oxycodone and its metabolites are eliminated primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; and conjugated oxymorphone ≤14%. Both free and conjugated noroxycodone have been found in urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life (mean ± SD) of oxycodone following administration of XARTEMIS XR was 4.5 ± 0.6 hours as compared to 3.9 ± 0.3 hours for immediate-release oxycodone.

Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen is excreted unchanged in urine. Following administration of XARTEMIS XR, the apparent elimination half-life is 5.8 ± 2.1 hours as compared to 4.1 ± 1.1 hours for immediate-release acetaminophen.

Special Populations

Age: Geriatric Population

Population pharmacokinetic studies indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in the pharmacokinetics of acetaminophen in elderly patients with normal renal and hepatic function.

Sex

Population pharmacokinetic analyses performed in a clinical study support the lack of gender effect on the pharmacokinetics of oxycodone.

Hepatic Impairment

The pharmacokinetics of XARTEMIS XR in patients with impaired hepatic function has not been studied. Oxycodone and acetaminophen are extensively metabolized, resulting in decreased clearance in patients with hepatic impairment [see Use in Specific Populations (8.6)].

Renal Impairment

The pharmacokinetics of Xartemis XR in patients with renal impairment has not been studied. Patients with renal impairment have higher plasma concentrations of oxycodone than subjects with normal renal function [see Use in Specific Populations (8.7)].

Post-Operative Bunionectomy Pain Study

Efficacy was demonstrated in one multicenter, randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose clinical trial comparing XARTEMIS XR and placebo in patients with acute pain following a unilateral first metatarsal bunionectomy. A total of 303 patients with a mean age of 43 (range 18 to 73) years, meeting criteria for randomization (pain intensity ≥4 on a 0 to 10 numerical pain rating scale) and receiving a fixed-dose of 2 tablets of XARTEMIS XR 7.5 mg oxycodone hydrochloride and 325 mg acetaminophen tablets or placebo every 12 hours over 48 hours were randomized. There were 36 early discontinuations (9% from XARTEMIS XR, 13% from placebo). Ibuprofen 400 mg every 4 hours as needed was allowed as rescue medication.

Mean baseline pain intensity scores were 6.2 in the XARTEMIS XR group (range: 4 to 10) and 6.0 in the placebo group (range: 1 to 10). Approximately 85% of the 150 subjects treated with XARTEMIS XR and 98% of the 153 subjects treated with placebo took rescue medication at least once for pain management during the 48 hours after the first dose. Median rescue medication use was 2 doses for XARTEMIS XR-treated subjects and 4 doses for placebo-treated subjects over the 48 hours; rescue medication was used by less than 50% of the XARTEMIS XR-treated patients after the first dose interval. Pain intensity was recorded at 2, 4, 8, and 12 hours after each dose, with additional recordings at 15, 30, 45, 60, and 90 minutes after the first dose. The median time to onset of pain relief was less than one hour for XARTEMIS XR. The primary endpoint was the summed pain intensity difference (change in pain from baseline) over 48 hours (SPID48), which demonstrated improvement in pain from baseline for the XARTEMIS XR treatment group compared to placebo.

Applies to acetaminophen / oxycodone: oral capsule, oral solution, oral tablet, oral tablet extended release

General

The most commonly reported adverse events have included lightheadedness, dizziness, drowsiness, sedation, nausea, and vomiting.[Ref]

Respiratory

Common (1% to 10%): Cough
Frequency not reported: Apnea, respiratory arrest, respiratory depression, hiccups
Postmarketing reports: Bronchospasm, dyspnea, hyperpnea, pulmonary edema, tachypnea, hypoventilation, laryngeal edema[Ref]

Hepatic

Oxycodone-acetaminophen:
Postmarketing reports: Transient elevations of hepatic enzymes, increased bilirubin, hepatic failure, jaundice, hepatotoxicity, hepatic disorder, hepatitis

Acetaminophen:
Frequency not reported: Hepatic necrosis[Ref]

At high doses, the most serious acetaminophen related adverse event is a dose-dependent, potentially fatal hepatic necrosis.[Ref]

Hypersensitivity

Frequency not reported: Skin eruptions, urticaria, erythematous skin reactions
Postmarketing reports: Anaphylaxis, allergic reaction, angioedema[Ref]

Dermatologic

Common (1% to 10%): Rash, blister, excoriation, pruritus, erythema
Frequency not reported: Dermatitis, ecchymosis, hyperhidrosis
Postmarketing reports: Urticaria, flushing, increased sweating[Ref]

Nervous system

Very common (10% or more): Dizziness (up to 13%)
Common (1% to 10%): Headache, somnolence
Frequency not reported: Lightheadedness, dizziness, drowsiness, sedation, migraine, myoclonus, paresthesia, tremor
Postmarketing reports: Stupor, cerebral edema, coma, subdural or intracranial hemorrhage, seizures

Opioids:
Postmarketing reports: Serotonin syndrome[Ref]

Psychiatric

Frequency not reported: Euphoria, dysphoria, insomnia, altered mood, sleep disorder, withdrawal syndrome
Postmarketing reports: Agitation, confusion, anxiety, mental impairment, drug dependence, drug abuse, depression, nervousness, hallucination, suicide[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 31%)
Common (1% to 10%): Vomiting, constipation, dry mouth, dyspepsia, diarrhea
Frequency not reported: Esophageal spasm, oropharyngeal pain, throat irritation
Postmarketing reports: Abdominal pain, abdominal distention, flatulence, gastrointestinal disorder, pancreatitis, intestinal obstruction, ileus, thirst[Ref]

Hematologic

Oxycodone-acetaminophen:
Frequency not reported: Thrombocytopenia, neutropenia, pancytopenia, hemolytic anemia

Acetaminophen:
Rare (0.01% to 0.1%): Agranulocytosis[Ref]

Renal

Postmarketing reports: Renal insufficiency and failure[Ref]

Cardiovascular

Common (1% to 10%): Edema
Frequency not reported: Hypotension, chest discomfort
Postmarketing reports: Tachycardia, dysrhythmias, orthostatic hypotension, bradycardia, palpitations, hypertension[Ref]

Metabolic

Frequency not reported: Decreased appetite
Postmarketing reports: Hypoglycemia, hyperglycemia, acidosis, alkalosis, hyperkalemia, dehydration

Musculoskeletal

Postmarketing reports: Rhabdomyolysis, myalgia

Ocular

Postmarketing reports: Miosis, visual disturbances, red eye

Genitourinary

Common (1% to 10%): Dysuria
Frequency not reported: Urinary retention, interstitial nephritis, proteinuria, decreased urine flow

Other

Postmarketing reports: Malaise, asthenia, fatigue, fever, hypothermia, accidental overdose, non-accidental overdose, hearing loss, tinnitus[Ref]

Endocrine

Adrenal insufficiency and androgen deficiency have been reported with opioid use, most often with chronic use.

Opioids:
Postmarketing reports: Adrenal insufficiency, androgen deficiency

Some side effects of Xartemis XR may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.