May 7, 2014
Let's Get the Facts Straight About Zohydro™ ER (hydrocodone bitartrate) Extended-Release Capsules, CII
Rampant misinformation about Zohydro™ ER continues to be reported by the media and echoed in Washington, D.C., and some states' capitals. These inaccurate and misleading statements are often made without proper context, and are intended to be sensational, to create fear, or to generate headlines. In many instances, these statements are not supported by scientific facts or medical evidence.
Let's get the facts straight.
Zohydro ER is the first and only extended-release hydrocodone without acetaminophen approved by the U.S. Food and Drug Administration (FDA) for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The fact is that Zohydro ER is a novel pain medicine that fills an important medical need—a hydrocodone medicine for severe chronic pain that can be taken twice a day, instead of 4-6 times a day, and that does not contain acetaminophen, which carries significant risk of liver toxicity when used for long periods of time.1
Acetaminophen overdose is a leading cause of acute liver failure in the U.S.2, with 63 percent of unintentional acetaminophen overdoses attributed to the use of opioid-acetaminophen combination products.3 The availability of an acetaminophen-free formulation of extended release hydrocodone, therefore, is an important therapeutic option for certain chronic pain patients.
FACT: Most other extended-release (ER) opioids are the same or more potent than Zohydro ER.
- Potency is a measure of a drug's activity in the body. Potency is compared on a morphine equivalent basis, a measurement that relates the potencies of different opioids to morphine.
- All extended-release medicines contain more milligrams of active ingredient per unit dose than comparable immediate-release versions because they are dosed less frequently each day.
- Hydrocodone in Zohydro ER has the same potency as hydrocodone in Vicodin (immediate-release hydrocodone). Therefore, Zohydro ER is not 10 times more potent than Vicodin.4
- So why different strengths? Zohydro ER is administered every 12 hours rather than every four to six hours like Vicodin. Therefore, to achieve the same total daily dose of hydrocodone, you would expect Zohydro ER to be of a greater dosage per unit than Vicodin and other immediate-release hydrocodone combination products. For example, a patient taking Vicodin 10 mg every four hours will have the same total daily dose of hydrocodone as a person taking Zohydro ER 30 mg every 12 hours.
Extended-Release vs. Immediate-Release Dosage Comparison1,5,6,7,8
FACT: The highest dosage strength of Zohydro™ ER is substantially lower than the highest dosage strength of oxycodone ER and morphine ER (on a per milligram basis).
- FDA Commissioner, Dr. Margaret Hamburg was quoted in a recent article in TIME9, clarifying this point:
"It's been said that Zohydro is super-potent. That surprises me because the highest dosage unit of Zohydro extended release is lower than the highest dosage unit of all the other available extended release products on a milligram basis."
- Oxycodone, the active medication in OxyContin®, has approximately the same potency as hydrocodone, the active medication in Zohydro ER and Vicodin®.6 However, OxyContin is available on the market in higher doses than Zohydro ER.
- Since oxycodone and hydrocodone have the same potency (based on morphine equivalents), they can be compared on a milligram basis. The highest strength of Zohydro ER is 50 mg and the highest strength of OxyContin is 80 mg. OxyContin is therefore available at a 60 percent higher strength than Zohydro ER. This holds true when the same comparison of Zohydro ER is made with all other extended-release opioid analgesics. (see graph below)
Potency and Strength Comparisons of ER Opioids1,5,6,7,8
FACT: The total quantity of Zohydro™ ER that could be available is less than 0.3 percent of the total amount of opioids that the DEA has allocated for 2014.10
- Many public health experts believe the risk for misuse and abuse of opioids is directly correlated to the amount of opioids sold each year—in other words, the more opioids are prescribed and dispensed, the greater the amount of opioids in the community and the greater the risk of misuse and abuse. The U.S. Drug Enforcement Administration (DEA) allocates quotas for each manufacturer of controlled drugs across the five classes of opioids, based on objective medical and scientific needs, including appropriate maintenance of inventory. For 2014, based on data from DEA, the total quota for these five categories combined is 326,000 kilograms, to be allocated to all manufacturers for extended and immediate release opioids.
- The amount of the DEA allocation requested and approved to manufacture Zohydro ER in 2014 is less than 1 percent of the total quota just based on hydrocodone and is less than 0.3 percent of the total DEA quota for all five categories of opioids as show in the chart below.
FACT: Only one of more than thirty extended-release opioids and none of the immediate-release opioids have FDA approved labeling for abuse deterrent properties.
FACT: In 2013, 98 percent of total opioid prescriptions were written for opioids that do not have FDA approved abuse deterrent properties.
- Only one extended-release opioid product has a new label claim that the formulation is "expected to make abuse via injection difficult and to reduce abuse via the intranasal route (snorting)" compared to a legacy non-abuse deterrent formulation of the same drug. However, that medication does not address the most acute form of abuse – which is oral (swallowing the medicine whole).11
- Abuse deterrent technology is in the early stages of development, as evidenced by only having one product which has received FDA labeling claims. As FDA Commissioner Margaret A. Hamburg, M.D., recently stated:12
"I would love if we had abuse-deterrent formulations that were actually meaningful and effective at deterring abuse in all instances. We are moving in that direction," Hamburg told lawmakers. "Right now, unfortunately, the technology is poor."
FACT: Zogenix has implemented voluntary initiatives, educational tools and safeguards, which began prior to making Zohydro™ ER available, unlike the introduction of opioids in the past.
- Zohydro ER is the first and only hydrocodone product that is currently prescribed and dispensed under Schedule II rules, the most restrictive schedule available under the U.S. Drug Enforcement Administration’s (DEA) Controlled Substances Act.
- Zogenix believes that the combination of scheduling, revised class-wide product labeling, the Extended-Release/Long-Acting (ER/LA) Opioids Risk Evaluation and Mitigation Strategy (REMS), and our comprehensive suite of voluntary initiatives that include distribution controls, prescriber, pharmacist, and patient educational programs and resources may be more effective to prevent misuse than existing abuse deterrent technologies.
- An External Safe Use Board of experts, including pain management, addiction and law-enforcement specialists, independently evaluate data, which will be shared with the FDA if patterns of abuse by prescribers, pharmacists or patients are detected.
- Sales representatives are compensated not on the number of prescriptions written, but instead for our representatives' efforts to ensure doctors, pharmacists and patients are educated on the risks and benefits of using extended-release opioids.
- Patients receive access to free locking pill bottle caps and discounted safe-storage units to help prevent others from obtaining unauthorized access to Zohydro ER.
The Bottom Line
Zohydro ER deserves to be judged on its medical merits and the benefits it provides to patients suffering from chronic pain, not on the basis of media reports. Over the coming weeks, we will continue to report and distribute accurate information to address common misperceptions about Zohydro ER.
On behalf of patients and the doctors who serve them, Zogenix will continue to demand due process and fair treatment for our medications and our company. We are dedicated to responsibly serving people suffering with severe chronic pain and the health care professionals who treat them, while doing our very best to set a new standard of transparency and commitment in delivering on our promise to patients.
- Zohydro™ ER Prescribing Information. ZohydroER.com.
- Larson AM et al. Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study. Hepatology 2005;42:1364-1372.
- Michna, E, Duh, MS, Korves, C, Dahl, JL. Removal of Opioid/Acetaminophen Combination Prescription Pain Medications: Assessing the Evidence for Hepatotoxicity and Consequences of Removal of These Medications. Pain Medicine. 2010; 11: 369-378.
- Vicodin® Prescribing Information.
- MS Contin® Prescribing Information.
- OxyContin® Prescribing Information.
- Exalgo® ER Prescribing Information.
- Opana® ER Prescribing Information.
- Park, Alice. FDA Expands Access to Overdose Antidote to Stem Opiate Addiction Epidemic. TIME. Apr 3, 2014. time.com/48841/fda-loosens-access-to-overdose- antidote-to-stem-opiate-addiction-epidemic.
- Federal Register, DEA Aggregate Production Quota History for Selected Substances. Updated October 2013.
- Katz N et al al. Tampering with Prescription Opioids: Nature and Extent of the Problem, Health Consequences and Solutions. Am J Drug Alcohol Abuse. 2011 Jul;37(4):205-17. doi: 10.3109/00952990.2011.569623. Epub 2011 Apr 26.
- Senate HELP Committee Hearing. “Protecting the Public Health: Examining FDA’s Initiatives and Priorities.” Dr. Margaret Hamburg. March 13, 2014.
About Zohydro® ER (hydrocodone bitartrate) Extended-Release Capsules, CII
Zohydro® ER is an extended-release opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term 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, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Zohydro ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Zohydro ER is not indicated for use as an as-needed (prn) analgesic.
Please see the Zohydro ER full prescribing information for the complete boxed warning and safety information.
WARNING: ADDICTION, ABUSE AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL; and CYTOCHROME P450 3A4 INTERACTION
- Zohydro ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions.
- Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow Zohydro ER whole to avoid exposure to a potentially fatal dose of hydrocodone.
- Accidental ingestion of Zohydro ER, especially in children, can result in a fatal overdose of hydrocodone.
- Prolonged use of Zohydro ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
- Instruct patients not to consume alcohol or any products containing alcohol while taking Zohydro ER because co-ingestion can result in fatal plasma hydrocodone levels.
- Initiation of CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone from Zohydro ER.
IMPORTANT SAFETY INFORMATION
Zohydro ER is contraindicated in patients with: significant respiratory depression; acute or severe bronchial asthma; known or suspected paralytic ileus; and hypersensitivity to hydrocodone bitartrate.
Zohydro ER warnings for: interactions with CNS depressants; elderly, cachectic, debilitated patients, and those with chronic pulmonary disease; hypotensive effects; patients with head injury or increased intracranial pressure; and concomitant use of CYP3A4 may increase opioid effects. Please see full prescribing information for the complete warning information.
Potential serious adverse events caused by opioids include addiction, abuse, and misuse; life-threatening respiratory depression; neonatal opioid withdrawal syndrome; interactions with other CNS depressants; hypotensive effects; gastrointestinal conditions, and seizures. The most common adverse reactions associated with Zohydro ER (≥2%) include constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, pruritus, abdominal pain, peripheral edema, upper respiratory tract infection, muscle spasms, urinary tract infection, back pain, and tremor.
Zogenix, Inc. (Nasdaq: ZGNX) is a pharmaceutical company committed to developing and commercializing therapies that address specific clinical needs for people living with pain-related conditions and central nervous system disorders who need innovative treatment alternatives to help them return to normal daily functioning.
Zohydro® ER is a registered mark of Zogenix, Inc.