ZohydroTM ER: Will the new hydrocodone formulation turn out to be a killer "pain"?
Bernadette Espiritu, PharmD Intern and Jennifer K. Seltzer, PharmD
Prescription opioid deaths have quadrupled over the last decade from approximately 4000 deaths in 1999 to 16,651 deaths in 2010.1 Drug poisoning, of which about 40% is attributed to opioid analgesics, was ranked the number one cause of unintentional injury death in adults between the ages of 25 and 65 in 2010, and, should trends continue, may become the number one cause of unintentional injury death over all age groups.1, 2
Hydrocodone bitartrate, a semi-synthetic opioid used to treat moderate to severe pain, is the most prescribed opioid in the country with nearly 143 million prescriptions dispensed in 2012 for hydrocodone-containing products in the United States alone.3-5 Until recently, hydrocodone was only available in combination with other medications such as acetaminophen, ibuprofen, and chlorpheneramine.5 While hydrocodone has analgesic and antitussive uses, abuse and misuse are common, which can result in addiction, dependence, and drug diversion.3 Despite the country's apparent "opioid epidemic", the FDA approved an extended-release capsule containing only hydrocodone bitartrate, marketed as ZohydroTM ER, in October 2013.4
ZohydroTM ER will be indicated for management of severe pain in patients who have ineffective or inadequate response or intolerance to alternative treatment options. It will be the first single-entity, extended-release hydrocodone formulation available to patients, providing pain relief lasting as long as 12 hours. Because of the high abuse potential and risk of addiction, ZohydroTM ER will enter the market as a Schedule II controlled substance. The formulation will be available in strengths of 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 50 mg of hydrocodone in hard gelatin capsules containing the medication in beads.4 In comparison, the current hydrocodone combination products contain a maximum of 10 mg of hydrocodone in each unit dose.5
The introduction of ZohydroTM ER to the market is associated with some controversy. First, the approval of ZohydroTM ER in October was announced one day after the FDA recommended rescheduling hydrocodone combination products to Schedule II controlled substances due to abuse potential, causing many to criticize the agency's seemingly contradictory stance on opioid addiction and abuse.6 In addition, this hydrocodone-only product was approved despite an FDA advisory committee voting 11-to-2 against ZohydroTM ER approval in December 2012.7 In an attempt to ensure appropriate medication use, ZohydroTM ER manufacturer, Zogenix, has established an External Safe-Use Board responsible for reviewing the medication's prescribing and use.8 Zogenix and the FDA assert that the benefits of the medication outweigh the potential risks.6
There are a number of possible concerns with the newest hydrocodone formulation. The product can be easily disassembled and crushed, providing addicts with the potential for more direct routes of medication administration, including snorting or injection.7 Additionally, ZohydroTM ER does not currently contain any abuse-deterrent properties. Abuse-deterrent formulations for opioids aim to maintain efficacy for patients using the medications for appropriate medical indications while preventing abuse from those using them for recreational purposes. Some strategies include creating pro-drug formulations or adding fillers that can prevent or discourage snorting or injecting the medication.9 The possibility of adding abuse-deterrents to ZohydroTM ER is currently being researched, but this formulation is still years away from FDA submission.6, 10 Finally, hydrocodone monotherapy dosage strengths as high as 50 mg are 5 to 10 times more potent than the highest hydrocodone-containing combination product on the market presently.4, 5 This has raised questions concerning possible risks for overdoses, especially in children who accidentally ingest the capsule or in patients who are opiate naïve.11 The potency of the new formulation, the ease at which it can be crushed, and the lack of abuse-deterrents has prompted over 40 organizations, and attorneys general from 29 states, to contact the FDA and request that they reconsider ZohydroTM ER's approval.6, 11, 12 Legislators have also spoken out against ZohydroTM ER's approval, introducing bills in the House and Senate to keep ZohydroTM ER off the market.12
Purdue Pharma, the maker of OxyContin®, has recently completed testing on a hydrocodone-only product that contains the abuse-deterrents critics have complained ZohydroTM ER's formulation lacks. Submission of this preparation for FDA consideration is planned for later this year. The introduction of this tamper-resistant formulation from Purdue Pharma may derail Zohydro™ ER prescribing and sales, and may provide extra ammunition for those who are requesting the FDA rethink the product's approval status.10
Should ZohydroTM ER become available in March, pharmacists are encouraged to exercise extra caution when verifying any ZohydroTM ER prescription that is brought to the pharmacy, especially in opioid naïve patients where filling the wrong dosage strength can lead to serious consequences. Counseling on the importance of keeping the medication out of the reach of children should be emphasized. Pharmacists should also be vigilant in identifying any fraudulent prescriptions, signs of drug abuse and misuse, and potential drug diversion.