Purdue Pharma L.P. Receives FDA Approval for HysinglaTM ER (hydrocodone bitartrate) Extended-Release Tablets CII, A Once-Daily Opioid Analgesic Formulated with Abuse-Deterrent Properties
Stamford, Conn. – November 20, 2014 – Purdue Pharma L.P. announced that the U.S. Food and Drug Administration (FDA) approved Hysingla ER (hydrocodone bitartrate) extended-release tablets CII, a once-daily, single-entity medication formulated using Purdue's proprietary extended-release solid oral platform, RESISTEC™. It is the first and only hydrocodone product to be recognized by the FDA as having abuse-deterrent properties that are expected to deter misuse and abuse via chewing, snorting and injection. However, abuse of Hysingla ER by the intravenous, intranasal, and oral routes is still possible.
Hysingla ER does not contain acetaminophen, the overuse of which has been reported to be a leading cause of acute liver failure in the United States.2,3 Prescription products containing hydrocodone and acetaminophen are both the most prescribed and among the most widely abused (nonmedical use) medications in the United States.4,5
"The burden of chronic pain and the abuse of prescription medications are both pressing societal problems," said Charles E. Argoff, MD, Professor of Neurology at Albany Medical College and Director of the Comprehensive Pain Center at Albany Medical Center in New York. "Opioids are an essential tool in our arsenal of medical treatments options, so greater availability and use of opioid analgesics with abuse-deterrent properties has the potential to help alleviate suffering among people with chronic pain while reducing the abuse of these medications. Furthermore, this product gives treatment providers the option to use hydrocodone without acetaminophen if they are concerned that their patients may be taking too much acetaminophen on a daily basis."
"We are proud to offer healthcare professionals and chronic pain patients another treatment option," said Mark Timney, CEO of Purdue Pharma L.P. "Hysingla ER is the third product in our pain management portfolio to receive an FDA label describing its abuse-deterrent characteristics. These innovations are an important step forward in helping meet patients' needs while also working to deter misuse and abuse."
Purdue expects to launch Hysingla ER in the United States in early 2015 in dosage strengths of 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg and 120 mg to be taken once every 24 hours.
Hysingla ER is 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. Hysingla ER has the following 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, Hysingla ER should be reserved 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. Hysingla ER is not indicated as an as-needed analgesic. Hysingla ER is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected paralytic ileus and gastrointestinal obstruction, and hypersensitivity to any component of Hysingla ER or the active ingredient, hydrocodone bitartrate.
Please see the Boxed Warning, Warnings and Precautions, and Adverse Reactions information below.
Abuse-Deterrence Testing and Labeling
Purdue conducted laboratory manipulation and extraction studies, and clinical abuse potential studies with Hysingla ER, in accordance with the FDA's 2013 Draft Guidance on Abuse‐Deterrent Opioids: Evaluation and Labeling. Based on the results of these studies, Hysingla ER is recognized by the FDA as having abuse-deterrent properties that are expected to deter misuse and abuse via chewing, snorting and injection, resulting in Tier 1 and 3 abuse-deterrence labeling. However, abuse of Hysingla ER by the intravenous, intranasal, and oral routes is still possible. The methodology and results of these studies are summarized in section 9.2 of the product's label.1 Additional data, including epidemiological data, when available, may provide further information on the impact of Hysingla ER on the abuse liability of the drug. Accordingly, section 9.2 may be updated in the future as appropriate.
Tier 1 labeling means that a product is formulated with physico-chemical barriers to abuse. To gain Tier 1 labeling, data from laboratory manipulation and extraction studies that assess how the abuse-deterrent properties of a formulation can be defeated or compromised are provided to the FDA. Tier 3 labeling means that the product is expected to result in a meaningful reduction in abuse. To gain Tier 3 labeling, data from clinical abuse potential studies are provided that assess the impact of a formulation's abuse-deterrent properties on measures that predict how probable it is that the formulation will be attractive to, or "liked" by, abusers. For Tier 4 labeling, the product must demonstrate reduced abuse in the community.6 Purdue will conduct post-marketing surveillance studies to assess this impact of the drug on reducing abuse and diversion in a real-world setting.
RESISTEC™ is Purdue Pharma's proprietary extended-release solid oral dosage formulation platform. RESISTEC uses a unique combination of polymer and processing that confers tablet hardness and imparts viscosity when dissolved in aqueous solutions.7
About Acetaminophen Toxicity
The use of products containing acetaminophen in high doses over a long period of time can cause severe liver injury, with reports of up to 63 percent of unintentional acetaminophen overdoses associated with the use of opioid-acetaminophen combination products.2,3 In January 2014, the FDA issued a statement that combination prescription pain relievers that contain more than 325 mg of acetaminophen per tablet, capsule, or other dosage unit should no longer be prescribed or dispensed because of a risk of liver damage if taken in doses exceeding the maximum recommended dose.8 According to the FDA statement, cases of severe liver injury have been reported in patients who took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period, took two or more acetaminophen-containing products simultaneously, or combined alcohol with acetaminophen.8
The Full Prescribing Information for Hysingla ER contains the following Boxed Warning:
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION
Addiction, Abuse, and Misuse
HYSINGLA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing HYSINGLA ER, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase. Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.2)].
Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of HYSINGLA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. 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 [see Warnings and Precautions (5.3)].
Cytochrome P450 3A4 Interaction
The concomitant use of HYSINGLA ER with all cytochrome P450 CYP3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.11) and Clinical Pharmacology (12.3)].
WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse
Hysingla ER contains hydrocodone, a Schedule II controlled substance. Hysingla ER exposes users to the risks of opioid addiction, abuse, and misuse. As extended-release products such as Hysingla ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Hysingla ER, and monitor all patients during therapy for the development of these behaviors or conditions. Abuse or misuse of Hysingla ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death.
Life‐Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with modified-release opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death. The risk of respiratory depression is greatest during the initiation of therapy or following a dose increase; therefore, closely monitor patients for respiratory depression. Proper dosing and titration of Hysingla ER are essential. Overestimating the Hysingla ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of Hysingla ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of Hysingla ER during pregnancy can result in neonatal opioid withdrawal syndrome which may be life-threatening to the neonate if not recognized and treated, and requires management according to protocols developed by neonatology experts.
Interactions with Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression, or death may result if Hysingla ER is used concomitantly with other CNS depressants, including alcohol or illicit drugs that can cause CNS depression. Start with a lower Hysingla ER dose than usual (i.e., 20-30% less), monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.
Use in Elderly, Cachectic, and Debilitated Patients and Patients with Chronic Pulmonary Disease
Closely monitor elderly, cachectic, and debilitated patients, and patients with chronic obstructive pulmonary disease because of the increased risk of life-threatening respiratory depression. Consider the use of alternative non-opioid analgesics in patients with chronic obstructive pulmonary disease if possible.
Use in Patients with Head Injury and Increased Intracranial Pressure
Monitor patients closely who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or impaired consciousness). Opioids may obscure the clinical course in a patient with a head injury. Avoid the use of Hysingla ER in patients with impaired consciousness or coma.
Hysingla ER may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. Monitor patients during dose initiation or titration. In patients with circulatory shock, Hysingla ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hysingla ER in patients with circulatory shock.
Gastrointestinal Obstruction, Dysphagia, and Choking
Use caution when prescribing Hysingla ER for patients who have difficulty swallowing, or have underlying gastrointestinal disorders that may predispose them to obstruction, dysphagia, or choking. Consider use of an alternative analgesic in these patients.
Decreased Bowel Motility
Hysingla ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of Hysingla ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis.
Cytochrome P450 CYP3A4 Inhibitors and Inducers
Concomitant use of CYP3A4 inhibitors may prolong opioid effects. Use with CYP3A4 inducers may cause lack of efficacy or development of withdrawal symptoms. If co-administration is necessary, evaluate patients frequently and consider dose adjustments until stable drug effects are achieved.
Driving and Operating Machinery
Hysingla ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
Interaction with Mixed Agonist/Antagonist Opioid Analgesics
Avoid the use of mixed agonist/antagonist analgesics in patients who have received or are receiving Hysingla ER, as they may reduce the analgesic effect and/or precipitate withdrawal.
QTc Interval Prolongation
QTc prolongation has been observed following daily doses of 160 mg of Hysingla ER. Avoid use in patients with congenital QTc syndrome. This observation should be considered in making clinical decisions regarding patient monitoring when prescribing Hysingla ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong QTc interval. In patients who develop QTc prolongation, consider reducing the dose.
Most common treatment-emergent adverse reactions (≥5%) reported by patients treated with Hysingla ER in the clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence.
The Full Prescribing Information for Hysingla ER, including the Boxed Warning and Medication Guide is available at www.purduepharma.com/hysinglaerpi.
About Purdue Pharma L.P.
Purdue Pharma L.P. and its associated U.S. companies are privately-held pharmaceutical companies known for pioneering research on chronic pain. Headquartered in Stamford, CT, Purdue is engaged in the research, development, production, and distribution of both prescription and over-the-counter medicines and hospital products. Additional information about Purdue can be found at www.purduepharma.com.
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1 Full Prescribing Information for HysinglaTM ER (hydrocodone bitartrate) Extended-Release Tablets CII
2 Larson et al. Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study. Hepatology. 2005; 42(6): 1364-1372.
3 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.
4 IMS Health NPA, based on TRx, August 2014. Accessed Oct. 20, 2014.
5 2013 National Survey on Drug Use and Health, Table 1.89A. Substance Abuse and Mental Health Services Administration. Accessed Oct. 20 2014.
6 Guidance for Industry: Abuse-Deterrent Opioids- Evaluation and Labeling: Draft Guidance. US Food & Drug Administration. Accessed Oct. 20, 2014.
7 Data on File, Purdue Pharma L.P.
8 Acetaminophen Prescription Combination Drug Products with more than 325 mg: FDA Statement – Recommendation to Discontinue Prescribing and Dispensing. U.S. Food & Drug Administration. Accessed Oct. 20, 2014.