IR formulations of oxycodone have long been available on the market dose consisting of oxycodone 15 mg with acetaminophen 650 mg, the.
This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA)-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone) with a nonopioid component. Keywords: opioid, analgesic, xartemis, acute postsurgical pain, substance abuse, acetaminophen, extended release Introduction. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen), are available solely in immediate-release (IR) formulations. Mary Hanna Bekhit1–5 1David Geffen School of Medicine, 2Ronald Reagan UCLA Medical Center, 3UCLA Ambulatory Surgery Center, 4UCLA Wasserman Eye Institute, 5UCLA Martin Luther King Community Hospital, University of California Los Angeles, Los Angeles, CA, USA Abstract: This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER) formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain.
One major efficacy study was published as a result of Phase III trials. Patients who received ER oxycodone/acetaminophen also reported lower pain intensity scores at several fixed time intervals postoperatively, compared with the placebo group. 7. This randomized, placebo-controlled, double-blind, multicenter study evaluated 303 patients undergoing unilateral first metatarsal bunionectomy. In this acute postsurgical pain model, fewer patients (85%) required ibuprofen rescue in the group that was randomized to receive two tablets of ER oxycodone/acetaminophen, when compared with the placebo group (98%).
10 Liver disease. Patients with a narrowed intestinal lumen may experience inability to pass the pill through the GI tract. An alternative analgesic regimen should be considered in patients with intestinal narrowing. Due to its chemical preparation, ER oxycodone/acetaminophen upon ingestion tends to swell and develop increased adhesiveness within the GI tract.
5 Despite the abundance of opioids available for treatment of acute pain, as well as the large variety of different classes of analgesics in addition to the opioid family, many patients still frequently experience undertreated acute pain. Recently, their popularity has soared, as the sales of opioid medications have quadrupled during the past decade. It contributes significantly to decreased function, thus translating more globally into decreased productivity and a noticeable cost burden to the US businesses. 6. 1 In addition to the obvious untoward emotional, social, and psychological effects of uncontrolled pain on the patient, this level of unmanaged intense pain bears significant negative consequences on the community as a whole. Opioid analgesics boast a well-established, long history as first-line therapy for acute surgical pain.
Table 1 Pharmacodynamic effects of oxycodone/acetaminophen ER Clinical studies.
The pharmacodynamic profile is similar to that of other opioid medications. The oxycodone component of ER oxycodone/acetaminophen contributes to the majority of the medication’s pharmacodynamic effects on the various organ systems listed in Table 1 (summarized from http://www.rxlist.com/xartemis-xr-drug.htm ).
Checked for plagiarism Yes Review by Single-blind.
Received 18 June 2015.
The pharmacological formulation of ER oxycodone/acetaminophen, by using several inactive ingredients, acts as a deterrent to abuse, by posing additional obstacles to chemically extracting the oxycodone component. 5. 5 This requires additional effort on the part of potential substance abusers, when compared to the more straightforward extraction of the active ingredient in other opioid pills.
11 ER oxycodone/acetaminophen should be used with caution in patients with adrenal insufficiency or Addison’s disease. Acute abdomen. Chronic opioid exposure may cause secondary hypogonadism, with associated sexual dysfunction, infertility, mood disorders, and osteoporosis.
Published 21 October 2015 Volume 2015:8 Pages 719—728 DOI http://dx.doi.org/10.2147/JPR.S73567.
Bulk reprints for the pharmaceutical industry.
Peer reviewers approved by Dr Kerui Gong.
10 Patients who have a known history of allergic reaction to other opioids should exercise caution, since little data exist regarding cross-reactivity for opioid hypersensitivity. 10 Effect on comorbidities Adrenal insufficiency. Patients who should not take ER oxycodone/acetaminophen include those who have experienced a prior allergic reaction or hypersensitivity to oxycodone, acetaminophen, or other component of the pharmaceutical composition, those with severe acute asthma or severe respiratory depression predisposing them to hypercarbia, and those with ileus.
6. The study authors sought to demonstrate a statistically significant improvement in analgesia when compared with placebo in post-bunionectomy patients over 48 hours, and they were able to document that the study met this primary endpoint. ER oxycodone/acetaminophen, previously the study drug MNK-795, received the FDA approval in March 2014 for the treatment of acute pain severe enough that other therapies are deemed not adequate. One important Phase III efficacy study contributed significantly to the approval by the FDA. 8 It was then marketed with the trade name Xartemis XR.
Several pharmacokinetic studies were conducted comparing ER oxycodone/acetaminophen with commonly used IR opioids, such as Roxicodone (oxycodone hydrochloride as a 5 mg, 15 mg, or 30 mg tablet), Ultracet (tramadol hydrochloride 37.5 mg with acetaminophen 325 mg), and Percocet (IR oxycodone 7.5 mg with acetaminophen 325 mg).
Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen), are available solely in immediate-release (IR) formulations. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA)-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action and multimodal analgesia through combination of an opioid (oxycodone) with a nonopioid component. This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER) formulation aimed at providing patients who are experiencing acute pain both immediate analgesia and continued, prolonged analgesia for up to 12 hours.
1 The second study evaluated ER oxycodone/acetaminophen in two-tablet doses every 12 hours compared to IR oxycodone alone, IR tramadol/acetaminophen, and IR oxycodone/acetaminophen in one-tablet doses every 6 hours. 1. Two of the studies were performed with healthy volunteers, with the first study comparing ER oxycodone/acetaminophen in both one- and two-tablet doses every 12 hours with IR oxycodone/acetaminophen in one-tablet doses every 6 hours.
7 In terms of the acetaminophen component, peak plasma levels are reached in approximay 1 hour from medication administration. The oxycodone component of the medication possesses an oral bioavailability of 60%–87%. 7. 7 This is similar to that of IR medications containing oxycodone, with both single and multiple doses. 7 Within 24 hours, or completion of two doses of ER oxycodone/acetaminophen (dosed every 12 hours), serum concentrations of both components of the medication achieve a steady state. 7 Detectable serum levels of oxycodone occur approximay 30 minutes from ingestion of the ER tablet, and maximum plasma concentrations ( C max ) are achieved approximay 3–4 hours after administration.
7 Acetaminophen’s volume of distribution is approximay 0.9 L/kg, and it exists in plasma in a 20% protein-bound state. 7 At normal body temperature (37°C) and pH (7.4), it exists in plasma in a 45% protein-bound state. 7 It distributes through most tissues with the exception of lipids. 7. When administered intravenously, oxycodone has a volume of distribution of 2.6 L/kg.
Significant rare side effects, some of which can be life-threatening, and occurring <1% of the time, include respiratory depression, withdrawal syndrome, palpitations, chest discomfort, cognitive dysfunction, memory impairment, excess sedation, migraine, hypersensitivity reaction, hypertension, myoclonus, and hypogonadism. 11, 12 Table 2 outlines more specific concerns regarding adverse side effects as well as their prevention and management. 10.
Therefore, the authors were able to demonstrate that the ER formulation does not present a higher addictive potential than IR formulations of oxycodone/acetaminophen. On the contrary, the ER formulation may actually prove less attractive to potential substance abusers in intact form or in chemically altered form. The study authors also investigated the crushed form of the ER pill and found that the crushed pill containing 30 mg oxycodone with 1,300 mg acetaminophen in ER form provided even more delayed subjective effects when compared with the crushed pill in IR form or the intact pill in ER form. 9 This final investigation sought to address the attempts at chemical alteration, including crushing, of narcotic pills by substance abusers to improve the subjective effects.
from submission to first editorial decision.
Table 2 Adverse side effect profile of extended-release oxycodone/acetaminophen Note: Data from US Food and Drug Administration. 21 Abbreviation: CNS, central nervous system. Contraindications.
7. Consumption of high-fat meals will delay peak serum levels by 2 hours, and consumption of low-fat meals with administration of the medication will delay peak serum levels by 1 hour. 7 Acetaminophen’s peak serum levels are reduced by approximay 23% by co-administration with a meal. 7 The oral bioavailability of oxycodone is increased by approximay 15%, and the peak plasma level increases by 12%–25% when the medication is administered with a meal.
1 In addition, the clinical effects were proportional to the doses administered with the ER formulation in one-tablet and two-tablet forms. 1. 1 They were also able to ascertain that the 12-hour ER dosing delivered less variable plasma levels of oxycodone and lower serum trough levels of acetaminophen, without increased incidence of adverse events. The authors of both studies were able to demonstrate similar plasma concentrations and steady-state pharmacokinetics for the ER formulation when compared with the various IR medication formulations.
Figure 1 Chemical structure of oxycodone (left), physical appearance of the tablet form of ER oxycodone/acetaminophen (middle), and chemical structure of acetaminophen (right). Abbreviations: MW, molecular weight; ER, extended release. Pharmacokinetics.
Editor who approved publication: Dr Michael E. Schatman.
5, 10 The potential for dependency or substance abuse should be assessed for each patient on an individual basis prior to administration of the medication. 5, 10 Reports exist of patients crushing, chewing, snorting, or injecting the dissolved form of the medication, which may result in the uncontrolled delivery of the oxycodone, overdose, and death. As with all narcotic medications, tolerance, chemical dependency, psychological dependency, addiction, and substance abuse may develop with chronic exposure to ER oxycodone/acetaminophen.
5 For example, the tablet transforms into a thick, gelatinous material when it dissolves into a liquid medium, thus making it difficult to aspirate into a syringe for intravenous abuse. 5 The tablet is also difficult to dissolve, break, or crush because of one of the inactive ingredients, polyethylene oxide; the formulation also presents a significant obstacle to “cooking” the tablet on a spoon. 5 Adverse reactions. 5 As a result of all these significant impediments to the chemical alteration of ER oxycodone/acetaminophen, recreational substance abusers may view this medication as a less attractive alternative to older opioids. The inclusion of several inactive ingredients within the large tablet of ER oxycodone/acetaminophen also poses yet another obstacle to substance abusers by making snorting or intravenous injection challenging. 5 It also makes snorting the drug difficult, since the humidity within the nasopharynx results in the same thick, sticky, pasty texture.
Both the oxycodone and acetaminophen components undergo extensive hepatic metabolism prior to primarily renal elimination. 7 The metabolites of acetaminophen are inert. 7 Pharmacodynamics. 7 The two major metabolites of oxycodone are noroxycodone and oxymorphone, as well as their glucuronides. 7 Noroxycodone is an active metabolite, possessing approximay 60% the potency of its parent compound, and oxymorphone circulates in very low levels in the plasma. 7 Acetaminophen undergoes three separate metabolic pathways in the liver: glucuronidation, conjugation with sulfate, or cytochrome P450-dependent oxidation.
Peer reviewer comments 2.
We offer real benefits to our authors, including fast-track processing of papers. Authors Bekhit MH.
10 Less frequent side effects, occurring 1%–10% of the time, include headache (10%), vomiting (9%), drowsiness (4%), constipation (4%), skin rash (2%), erythema (1%), excoriation (1%), pruritis (1%), skin blistering (1%), peripheral edema (1%), dysuria (1%), hot flashes (1%), elevated liver enzymes, diarrhea, dyspepsia, xerostomia, fatigue, insomnia, and cough. Some of the more common side effects, occurring with an incidence greater than 10%, include dizziness and nausea. Adverse side effects of ER oxycodone/acetaminophen can be categorized in terms of frequency of occurrence. 10.
Pharmacology and substance abuse.
Open access peer-reviewed scientific and medical journals.
10 Biliary obstruction. Signs/symptoms may be masked by administration of ER oxycodone/acetaminophen.
10 GI pathology. These patients may experience adverse intracranial effects associated with hypercarbia. ER oxycodone/acetaminophen may potentiate CO 2 retention caused by hypoventilation and as such should be used with caution in patients with central nervous system depression or coma.
Hepatotoxicity is associated with acetaminophen dosing greater than 4 g/day, as well as long-term exposure to ER oxycodone/acetaminophen. Patients with alcohol-related hepatic disease, particularly those consuming more than three alcoholic beverages per day, are at increased risk of hepatotoxicity. 10 Substance abuse.
Dove Medical Press is a member of the OAI.
5 Although the FDA-approved label for ER oxycodone/acetaminophen does not specifically make use of language cautioning against or deterring from narcotic abuse, Mallinckrodt continued to work closely with the FDA during the Phase I trial period to “develop more data to characterize abuse-deterrence features of Xartemis XR and other products utilizing this technology platform”. 9. As opioid sales have dramatically increased recently over the past decade, so has the potential for substance abuse. 6 The pharmaceutical company continued to conduct several studies addressing the abuse potential of the medication, and was able to demonstrate that the ER formulation had no more, and in fact less, of an addictive potential, which they quantified in the study as “drug liking” and “drug high” measured by visual analog scales, than the IR formulation that had already been available on the market for many years.
3 Further estimates by the Institute of Medicine from 2011 suggest that approximay 80% of patients undergoing surgery experienced postoperative pain, and that approximay 88% of these surgical patients described the acute postsurgical pain as ranging from moderate to severe or extreme. 4. Each year, approximay 25–97 million patients in the USA experience acute pain. 1 Based on estimates from the Centers for Disease Control, in the year 2010, approximay a little over 102 million surgical procedures were ordered or performed at office visits. 2 In addition, another 51 million surgeries were performed in this same year on an inpatient basis.
Patients with biliary duct disease should use ER oxycodone/acetaminophen with caution, as it may cause Sphincter of Oddi spasm and worsen biliary tract dysfunction, with possible progression to acute pancreatitis. 7, 10 Altered mental status.
ER oxycodone/acetaminophen comprises a combination of the opioid oxycodone hydrochloride 7.5 mg and the nonopioid analgesic acetaminophen 325 mg. The tablet allows dosing every 12 hours instead of every 4–6 hours, and it utilizes a dual-layer biphasic delivery mechanism that contains both IR and delayed-release layers, or components. 1. It provides a much improved duration of action when compared with the previously available IR formulation of oxycodone/acetaminophen. 1 When two tablets are administered as a single dose consisting of oxycodone 15 mg with acetaminophen 650 mg, the medication is designed to deliver oxycodone 3.75 mg and acetaminophen 325 mg through the IR component as well as oxycodone 11.25 mg and acetaminophen 325 mg through the ER component, which continually delivers the medication in the upper gastrointestinal (GI) tract at a steady rate.
*Business days (Mon-Fri) Papers Published. from editorial acceptance to publication.
Accepted for publication 3 July 2015.
1 The combination of oxycodone and acetaminophen in IR formulations has a long-standing history of therapeutic use for moderate-to-severe pain. 1 Due to the short-acting nature of the IR pill, it again requires frequent redosing every 4–6 hours, similar to IR oxycodone alone. The main goal of this multimodal analgesic regimen is to achieve therapeutic benefit while using reduced doses of each individual medication in order to minimize toxic side effects. ER formulations of oxycodone, though not in combination with acetaminophen, have offered the advantage of longer dosing intervals and thus the convenience of less frequent dosing. 1 Opioids often are supplied as a combination pill including a nonopioid analgesic, most commonly acetaminophen. Oxycodone, or 4,5-alpha-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6-one hydrochloride, is an opioid agonist derived from the opium alkaloid thebaine. IR formulations of oxycodone have long been available on the market for management of moderate-to-severe pain, with frequent dosing intervals – usually every 4–6 hours. 7 It is a schedule II controlled substance, with significant potential for abuse.
It compared the “positive subjective drug effects” of the ER formulation of oxycodone/acetaminophen with those of the IR formulation. 9. 9 The comparison between formulations looked at two dosages, 15 mg oxycodone with 650 mg acetaminophen and 30 mg oxycodone with 1,300 mg acetaminophen, and found similar results regardless of dose administered. One of the Phase I trials of ER oxycodone/acetaminophen was published in August 2014. This randomized, double-blind, placebo-controlled trial was conducted on 55 healthy volunteers, and was able to demonstrate that the ER formulation resulted in delayed peak effects, lower peak effects, and lower drug liking scores measured by visual analog scale than the IR formulation of oxycodone/acetaminophen.
open access to scientific and medical research.