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VBCN - November 2016 Volume 3, No 3 - Drug Update
Lisa A. Raedler, PhD, RPh

Opioid analgesics are among the most often prescribed drug classes in the United States. The National Institute on Drug Abuse estimated that in 2014, US pharmacies dispensed 245 million prescriptions for opioids for the treatment of patients with acute or chronic pain.1

Estimates of the prevalence of chronic pain vary from 39 million to 100 million American adults.2,3 The prevalence is higher among women, individuals aged 60 to 69 years, those who rate their health as fair or poor, people who are overweight or obese, and those who were hospitalized at least once in the preceding year.2

A well-established challenge with opioid analgesics is their propensity to be diverted and improperly used, resulting in a national epidemic of opioid overdose, deaths, and addictions.4

When opioids are abused, they are typically taken at higher doses than originally prescribed or are crushed for a more intense drug effect. Abuse-deterrent formulations have been developed with the goal of minimizing the likelihood that they will be injected, snorted, or taken at higher doses than prescribed.5

The US Food and Drug Administration (FDA) has approved several oral abuse-deterrent formulations of opioid medications, including oxycodone (OxyContin), oxycodone and naloxone extended-release (ER) tablets (Targiniq ER), morphine sulfate and naltrexone ER capsules (Embeda), and hydrocodone ER tablets (Hysingla ER). Other opioids are not approved as abuse-deterrent formulations, and cannot be crushed or extracted.4

FDA Approves Abuse-Deterrent Oxycodone Analgesic for Chronic Pain

On April 26, 2016, the FDA approved oxycodone ER capsules (Xtampza ER; Collegium Pharmaceutical), a twice-daily analgesic medication, for the management of patients with chronic pain that is severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.6,7

Oxycodone ER capsules use DETERx technology to provide adequate pain control while maintaining its drug-release profile despite being subjected to common methods of manipulation, including chewing and crushing the drug before administration.6

“Abuse-deterrent opioids are a critical component to fighting the widespread national epidemic of prescription opioid abuse,”6 said Jeffrey Gudin, MD, Director of Pain Management and Palliative Care, Englewood Hospital and Medical Center, NJ, in the company’s press release announcing the approval. “The FDA approval of Xtampza ER is incredibly timely as abuse and misuse of opioids is at an all-time high.”6

Mechanism of Action

Oxycodone, a full opioid agonist, is relatively selective for the mu receptor. As with all full opioid agonists, there is no ceiling effect to oxycodone’s analgesia.7

The precise mechanism of oxycodone’s analgesic action is not known; however, specific central nervous system (CNS) opioid receptors for endogenous compounds with opioidlike 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.7

Dosing and Administration

Oxycodone ER capsules are available in dosings of 9 mg (equivalent to 10-mg oxycodone hydrochloride [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 20-mg oxycodone HCl).7

The recommended dosage of oxycodone ER capsules varies depending on the patient’s level of experience with opioids. When oxycodone ER is prescribed for opioid-naïve patients or for patients who are not opioid-tolerant, the recommended dosage is 9 mg orally every 12 hours, with food.7

When starting oxycodone ER capsules treatment in patients receiving non–oxycodone-containing around-the-clock opioid drugs, all such medications should be discontinued. Because no established conversion ratios for switching from other opioids to oxycodone ER have been defined, oxycodone ER capsules should be started at a dosage of 9 mg orally every 12 hours, with food.7

Patients receiving other oral oxycodone formulations can be converted to oxycodone ER capsules using the same total daily dose of oxycodone by administering 50% of the patient’s total daily dose of oxycodone as oxycodone ER every 12 hours, with food.7 Because oxycodone ER capsules are not bioequivalent to other oxycodone ER drugs, patients should be monitored, and dosages should be adjusted as needed.7

Oxycodone ER capsules should not be discontinued abruptly. When a patient no longer requires oxycodone ER capsules, a gradual downward titration can prevent withdrawal. Patients should always take oxycodone ER capsules with food and with approximately the same amount of food to ensure that consistent plasma levels are achieved.7

For patients who have difficulty swallowing, oxycodone ER capsules can be opened and sprinkled on soft foods, or into a cup for administration directly into the mouth or through a gastrostomy or nasogastric feeding tube.7

Clinical Trials

The efficacy of oxycodone ER capsules was established in an enriched-enrollment, randomized-withdrawal, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial involving 740 patients with persistent, moderate-to-severe chronic lower back pain whose pain control from their previous therapy was inadequate. All patients discontinued previous opioid and/or nonopioid analgesics before enrolling in the study.7,8

During the first 6 weeks of this study, the dosage was titrated in an open-label fashion to a stable and tolerated dose of oxycodone ER capsules, ranging from 18 mg (equivalent to 20-mg oxycodone HCl) twice daily to 72 mg (equivalent to 80-mg oxycodone HCl) twice daily. The use of rescue medication, acetaminophen (up to two 500-mg tablets every 4 to 6 hours for a 2000 mg maximum) was optional.7

After titration, 389 patients entered the 12-week, double-blind, maintenance phase, in which they were randomized to receive a fixed dose of oxycodone ER capsules, or matching placebo. In the latter group, oxycodone ER capsules were tapered in a blinded fashion according to a prespecified schedule. All patients were allowed to use rescue medication (acetaminophen, maximum of 2000 mg daily).7

The double-blind maintenance phase was completed by 122 patients who received oxycodone ER capsules and 100 patients who received placebo.7 The primary efficacy results showed a significant difference in the average pain intensity from randomization to week 12 between the patients receiving oxycodone ER capsules and the placebo group (mean, –1.56; P <.0001).8

The daily dose of oxycodone ER capsules ranged from 36 mg to 144 mg, equivalent to 40 mg to 160 mg of oxycodone HCl.7

Adverse Events

The safety of oxycodone ER capsules was evaluated in a phase 3 randomized clinical trial in which 740 patients underwent titration, and 193 patients received oxycodone ER capsules in the maintenance phase. The most common (>5%) adverse events with oxycodone ER capsules during the 6-week titration phase and the 12-week maintenance phase included nausea, headache, constipation, somnolence, pruritus, vomiting, and dizziness (Table).7

Table

During the maintenance phase, 4% of patients who received oxycodone ER capsules discontinued treatment because of a lack of efficacy, and 7% of patients discontinued treatment because of adverse events.7

Contraindications

Oxycodone ER capsules are contraindicated in patients with significant respiratory depression; those with acute or severe bronchial asthma in an unmonitored setting or when resuscitative equipment is not present; in patients with known or suspected gastrointestinal obstruction, including paralyticileus; and/or in patients with hyper­sen­sitivity, including anaphylaxis, to oxycodone.7

Warnings and Precautions

Oxycodone ER capsules is a schedule II controlled substance. The FDA approved it with a Boxed Warning to inform prescribers of the medication’s serious risk for addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; and cytochrome (CY) P450 3A4 interactions.6,7

In addition, there is an increased risk for overdose and death with ER drugs, including oxycodone ER capsules, because of the increased amount of oxycodone present. Abuse or misuse by snorting or injecting oxycodone ER capsules can result in overdose and death.7

Although serious, life-threatening or fatal respiratory depression can occur at any time during the use of oxycodone ER capsules, the risk is greatest after initiation and after a dose increase. The proper dosing and titration of oxycodone ER capsules are essential.7

Accidental ingestion of just one dose of oxycodone ER capsules, especially by children, can cause respiratory depression and death as a result of oxycodone overdose.7

The prolonged use of oxycodone ER capsules during pregnancy can result in neonatal withdrawal syndrome in the neonate, which can be life-threatening if not recognized and treated by experts. Newborns should be observed for signs of withdrawal syndrome and be managed accordingly.7

When using CYP3A4 inhibitors (eg, macrolide antibiotics, azole-antifungal agents, protease inhibitors) or when a CYP3A4 inducer (eg, rifampin, carbamazepine, phenytoin) is discontinued, patients receiving oxycodone ER capsules may require dose reductions to achieve stable drug effects.7

When using oxycodone ER capsules with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, patients may require dose increases to maintain adequate analgesia or to mitigate the symptoms of opioid withdrawal.7

If used concomitantly with a CNS-depressant drug (eg, benzodiazepines, other sedative-hypnotics, anxiolytics), oxycodone ER capsules should be started at 33% to 50% of the recommended dose. A lower dose of the concomitant CNS-depressant drug may be required. An alternative analgesic should be prescribed for patients who require a dose of oxycodone ER capsules <9 mg.7

Even at the recommended dosages of oxycodone ER capsules, patients with significant chronic obstructive pulmonary disease, cor pulmonale, poor respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at risk for decreased respiratory drive and apnea. Elderly, cachectic, and debilitated patients are at an increased risk for life-threatening respiratory depression.7

Adrenal insufficiency can occur with opioid use; treatment with corticosteroids and weaning patients off the opioid dose is recommended.7

The risk for severe hypotension is higher in patients with compromised blood pressure by reduced blood volume or by use of CNS-depressant drugs (eg, phenothiazines, general anesthetics). Such patients should be monitored for signs of hypotension after initiating or titrating the dosage of oxycodone ER capsules. Oxycodone ER capsules should not be used in patients with circulatory shock.7

In patients with evidence of increased intracranial pressure or brain tumors, the use of oxycodone ER capsules can reduce respiratory drive and increase intracranial pressure. Oxycodone ER capsules are not recommended for patients with impaired consciousness or coma.7

Oxycodone can cause spasm of the sphincter of Oddi. Patients with biliary tract disease, including acute pancreatitis, should be monitored for worsening symptoms.7

Oxycodone may increase the frequency of and risk for seizures in patients with seizure disorders.7

Mixed agonist–antagonist drugs (eg, pentazocine, nalbuphine, butorphanol) and partial agonist analgesics (eg, buprenorphine) should be avoided when using a full opioid agonist analgesic, including oxycodone ER capsules. These drugs can reduce the analgesic effect of oxycodone ER capsules and/or precipitate withdrawal symptoms.7

Oxycodone can impair mental and physical abilities that are needed to perform potentially hazardous activities (eg, driving a car, operating machinery).7

If a patient receiving oxycodone ER capsules undergoes urine testing for oxycodone, caution should be used in interpreting the results.7

Use in Specific Populations

Women of reproductive potential should be advised about the increased risk for fetal harm associated with the use of oxycodone ER capsules.7 The long-term use of opioid drugs may compromise fertility in men and women.7 Breast-feeding is not recommended while taking oxycodone ER capsules.7

Oxycodone ER capsules has not been studied in pediatric patients aged <18 years.7

Elderly patients should start oxycodone ER capsules at the low end of the dosing range. Respiratory depression is the chief risk in elderly patients receiving opioids.7

Because plasma oxycodone concentrations are elevated in individuals with hepatic impairment, dosing of oxycodone ER capsules should be initiated at 33% to 50% of the usual starting dose and followed by careful dose titration.7

Because plasma oxycodone concentrations are elevated in people with renal impairment, conservative dosing of oxycodone ER capsules is recommended, followed by careful dose titration.7

Oxycodone plasma exposures can be up to 20% higher in healthy women compared with healthy men, even after accounting for differences in weight and body mass index. In the phase 3 clinical trial of oxycodone ER capsules, women were more likely than men to report typical opioid-related adverse events.7 No differences in drug efficacy were noted between men and women.7

Conclusion

For patients with chronic pain who have not obtained adequate pain relief with previous therapy, oxycodone ER capsules offer a safe and effective option that may deter misuse and abuse. Oxycodone ER capsules are the only ER, abuse-deterrent capsule formulation of oxycodone that can be opened and sprinkled on food for patients who are unable to swallow pills.

Copyright © 2016 American Health & Drug Benefits. Used with permission.




References

  1. National Institute on Drug Abuse. The latest prescription trends for controlled prescription drugs. www.drugabuse.gov/news-events/meetings-events/2015/09/latest-prescription-trends-controlled-prescription- drugs. Accessed August 5, 2016.
  2. Kennedy J, Roll JM, Schraudner T, et al. Prevalence of persistent pain in the U.S. adult population: new data from the 2010 National Health Interview Survey. J Pain. 2014;15:979-984.
  3. Institute of Medicine Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011. www.ncbi.nlm.nih.gov/books/NBK91497/pdf/Bookshelf_NBK91497.pdf. Accessed August 5, 2016.
  4. Volkow ND, McLellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med. 2016;374:1253-1263.
  5. Mastropietro DJ, Omidian H. Abuse-deterrent formulations: part 2: commercial products and proprietary technologies. Expert Opin Pharmacother. 2015;16:305-323.
  6. Collegium Pharmaceutical. Collegium receives FDA approval Xtampza ER, an Analgesic with Abuse-Deterrent Properties for the Treatment of Chronic Pain. Press release. http://ir.collegiumpharma.com/phoenix.zhtm l?c=253995&p=irol-newsArticle&ID=2161728. April 26, 2016. Accessed November 4, 2016.
  7. Xtampza ER (oxycodone) extended-release capsules [prescribing information]. Cincinnati, OH: Collegium Pharmaceutical; April 2016.
  8. Katz N, Kopecky EA, O’Connor M, et al. A phase 3, multicenter, randomized, double-blind, placebo-controlled, safety, tolerability, and efficacy study of Xtampza ER in patients with moderate-to-severe chronic low back pain. Pain. 2015;156:2458-2467.
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