YOUR PATIENTS' HYDROCODONE NEEDS VARY THEIR ER HYDROCODONE DOESN'T HAVE TO

Addressing addiction, abuse, and misuse

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hysingla ER, and monitor all patients receiving Hysingla ER for the development of these behaviors and conditions

Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Hysingla ER for the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids such as Hysingla ER, but use in such patients necessitates intensive counseling about the risks and proper use of Hysingla ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Risks specific to abuse of Hysingla ER

  • Hysingla ER contains hydrocodone, a substance with a high potential for abuse similar to other opioids, including fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. The high drug content in the extended-release formulation adds to the risk of adverse outcomes from abuse and misuse

  • All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use

  • Hysingla ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised

  • Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs


Risk Evaluation and Mitigation Strategy (REMS)

Hysingla ER is subject to the REMS for extended-release and long-acting (ER/LA) opioid analgesics

The goal of the REMS is to reduce serious adverse outcomes resulting from inappropriate prescribing, abuse, and misuse of ER/LA opioid analgesics, while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.

Hysingla ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Documentation and maintenance of careful prescribing and treatment records are essential, and should include:

  • Physician and patient agreement

  • Proper assessment of the patient

  • Proper prescribing practices

  • Periodic reevaluation of therapy

  • Proper dispensing and correct storage and handling

  • Careful record keeping of prescribing information, including quantity, frequency, and renewal requests, is strongly advised

  • Providing patient and/or caregiver with the Medication Guide

  • Reviewing the Opioid REMS Patient Counseling Document with the patient and/or caregiver at the time of prescribing

For more information, including REMS-compliant educational CME/CE programs on safe prescribing of ER/LA opioid analgesics, visit ER‑LA‑OpioidREMS.com.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS

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 and 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

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 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions 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 (5.4), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5), Drug Interactions (7)].

  • Reserve concomitant prescribing of Hysingla ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.

Indications and usage

Hysingla® ER (hydrocodone bitartrate) 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.

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 Hysingla 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.
  • Hysingla ER is not indicated as an as-needed (prn) analgesic.
Contraindications
  • 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 gastrointestinal obstruction, including paralytic ileus; hypersensitivity to hydrocodone or any component of Hysingla ER.
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. Because 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.
  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hysingla ER. 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 receiving Hysingla ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hysingla ER, but use in such patients necessitates intensive counseling about the risks and proper use of Hysingla ER along with intensive monitoring for signs of addiction, abuse, and misuse.
  • 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.
  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hysingla ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.
Life-Threatening Respiratory Depression
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.
  • While serious, life‐threatening, or fatal respiratory depression can occur at any time during the use of Hysingla ER, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression especially within the first 24–72 hours of initiating therapy with and following dosage increases of Hysingla ER.
  • To reduce the risk of respiratory depression, proper dosing and titration of Hysingla ER are essential. Overestimating the Hysingla ER dosage 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 withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
  • Concomitant use with a CYP3A4 inhibitor, such as macrolide antibiotics, azole-antifungal agents, and protease inhibitors, particularly when an inhibitor is added after a stable dose of Hysingla ER is achieved, and discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression. Monitor patients closely at frequent intervals and consider dosage reduction of Hysingla ER until stable drug effects are achieved. Concomitant use of Hysingla ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. Monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.
Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hysingla ER with benzodiazepines or CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
  • Advise both patients and caregivers about the risks of respiratory depression and sedation when Hysingla ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or Elderly, Cachectic, or Debilitated Patients
  • The use of Hysingla ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Hysingla ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hysingla ER.
  • Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
  • Monitor such patients closely, particularly when initiating and titrating Hysingla ER and when Hysingla ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
Adrenal Insufficiency
  • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.
Severe Hypotension
  • Hysingla ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hysingla ER. 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.
QTc Interval Prolongation
  • QTc prolongation has been observed with Hysingla ER following doses of 160 mg. This observation should be considered in making decisions regarding patient monitoring when prescribing Hysingla ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong QTc interval.
  • Hysingla ER should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33–50%, or changing to an alternate analgesic.
Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
  • In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hysingla ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor those patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hysingla ER. 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.
Gastrointestinal Obstruction, Dysphagia, and Choking
  • In the clinical studies with specific instructions to take Hysingla ER with water to swallow the tablets, 11 out of 2476 subjects reported difficulty swallowing Hysingla ER. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet. Instruct patients not to pre-soak, lick or otherwise wet Hysingla ER tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen.
Risks of Use in Patients with Gastrointestinal Conditions
  • Hysingla ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydrocodone in Hysingla ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis.
Increased Risk of Seizures in Patients with Seizure Disorders
  • The hydrocodone in Hysingla ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hysingla ER therapy.
Withdrawal
  • Avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hysingla ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing Hysingla ER, gradually taper the dosage. Do not abruptly discontinue Hysingla ER.
Risks of Driving and Operating Machinery
  • Hysingla ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14–16 hours (range 6–30 hours) after initial dosing of Hysingla ER. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hysingla ER and know how they will react to the medication.
ADVERSE REACTIONS
  • The most common adverse reactions (≥5%) reported by patients treated with Hysingla ER in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence.

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Indications and Usage

Indications and usage

Hysingla® ER (hydrocodone bitartrate) 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.

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 Hysingla 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.
  • Hysingla ER is not indicated as an as-needed (prn) analgesic.
Important Safety Information

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS

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 and 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

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 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions 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 (5.4), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5), Drug Interactions (7)].

  • Reserve concomitant prescribing of Hysingla ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.
Contraindications
  • 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 gastrointestinal obstruction, including paralytic ileus; hypersensitivity to hydrocodone or any component of Hysingla ER.
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. Because 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.
  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hysingla ER. 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 receiving Hysingla ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hysingla ER, but use in such patients necessitates intensive counseling about the risks and proper use of Hysingla ER along with intensive monitoring for signs of addiction, abuse, and misuse.
  • 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.
  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hysingla ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.
Life-Threatening Respiratory Depression
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.
  • While serious, life‐threatening, or fatal respiratory depression can occur at any time during the use of Hysingla ER, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression especially within the first 24–72 hours of initiating therapy with and following dosage increases of Hysingla ER.
  • To reduce the risk of respiratory depression, proper dosing and titration of Hysingla ER are essential. Overestimating the Hysingla ER dosage 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 withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
  • Concomitant use with a CYP3A4 inhibitor, such as macrolide antibiotics, azole-antifungal agents, and protease inhibitors, particularly when an inhibitor is added after a stable dose of Hysingla ER is achieved, and discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression. Monitor patients closely at frequent intervals and consider dosage reduction of Hysingla ER until stable drug effects are achieved. Concomitant use of Hysingla ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. Monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.
Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hysingla ER with benzodiazepines or CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
  • Advise both patients and caregivers about the risks of respiratory depression and sedation when Hysingla ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or Elderly, Cachectic, or Debilitated Patients
  • The use of Hysingla ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Hysingla ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hysingla ER.
  • Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
  • Monitor such patients closely, particularly when initiating and titrating Hysingla ER and when Hysingla ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
Adrenal Insufficiency
  • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.
Severe Hypotension
  • Hysingla ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hysingla ER. 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.
QTc Interval Prolongation
  • QTc prolongation has been observed with Hysingla ER following doses of 160 mg. This observation should be considered in making decisions regarding patient monitoring when prescribing Hysingla ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong QTc interval.
  • Hysingla ER should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33–50%, or changing to an alternate analgesic.
Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
  • In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hysingla ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor those patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hysingla ER. 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.
Gastrointestinal Obstruction, Dysphagia, and Choking
  • In the clinical studies with specific instructions to take Hysingla ER with water to swallow the tablets, 11 out of 2476 subjects reported difficulty swallowing Hysingla ER. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet. Instruct patients not to pre-soak, lick or otherwise wet Hysingla ER tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen.
Risks of Use in Patients with Gastrointestinal Conditions
  • Hysingla ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydrocodone in Hysingla ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis.
Increased Risk of Seizures in Patients with Seizure Disorders
  • The hydrocodone in Hysingla ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hysingla ER therapy.
Withdrawal
  • Avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hysingla ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing Hysingla ER, gradually taper the dosage. Do not abruptly discontinue Hysingla ER.
Risks of Driving and Operating Machinery
  • Hysingla ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14–16 hours (range 6–30 hours) after initial dosing of Hysingla ER. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hysingla ER and know how they will react to the medication.
ADVERSE REACTIONS
  • The most common adverse reactions (≥5%) reported by patients treated with Hysingla ER in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence.

Intended for healthcare professionals of the United States of America only.

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WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS

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 and 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

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 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions 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 (5.4), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5), Drug Interactions (7)].

  • Reserve concomitant prescribing of Hysingla ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.

Indications and usage

Hysingla® ER (hydrocodone bitartrate) 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.

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 Hysingla 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.
  • Hysingla ER is not indicated as an as-needed (prn) analgesic.
Contraindications
  • 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 gastrointestinal obstruction, including paralytic ileus; hypersensitivity to hydrocodone or any component of Hysingla ER.
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. Because 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.
  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hysingla ER. 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 receiving Hysingla ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hysingla ER, but use in such patients necessitates intensive counseling about the risks and proper use of Hysingla ER along with intensive monitoring for signs of addiction, abuse, and misuse.
  • 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.
  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hysingla ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug.
Life-Threatening Respiratory Depression
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended, and if not immediately recognized and treated, may lead to respiratory arrest and death.
  • While serious, life‐threatening, or fatal respiratory depression can occur at any time during the use of Hysingla ER, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression especially within the first 24–72 hours of initiating therapy with and following dosage increases of Hysingla ER.
  • To reduce the risk of respiratory depression, proper dosing and titration of Hysingla ER are essential. Overestimating the Hysingla ER dosage 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 withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
  • Concomitant use with a CYP3A4 inhibitor, such as macrolide antibiotics, azole-antifungal agents, and protease inhibitors, particularly when an inhibitor is added after a stable dose of Hysingla ER is achieved, and discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression. Monitor patients closely at frequent intervals and consider dosage reduction of Hysingla ER until stable drug effects are achieved. Concomitant use of Hysingla ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. Monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur.
Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hysingla ER with benzodiazepines or CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
  • Advise both patients and caregivers about the risks of respiratory depression and sedation when Hysingla ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or Elderly, Cachectic, or Debilitated Patients
  • The use of Hysingla ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Hysingla ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hysingla ER.
  • Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
  • Monitor such patients closely, particularly when initiating and titrating Hysingla ER and when Hysingla ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
Adrenal Insufficiency
  • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.
Severe Hypotension
  • Hysingla ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hysingla ER. 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.
QTc Interval Prolongation
  • QTc prolongation has been observed with Hysingla ER following doses of 160 mg. This observation should be considered in making decisions regarding patient monitoring when prescribing Hysingla ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong QTc interval.
  • Hysingla ER should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33–50%, or changing to an alternate analgesic.
Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
  • In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hysingla ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor those patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hysingla ER. 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.
Gastrointestinal Obstruction, Dysphagia, and Choking
  • In the clinical studies with specific instructions to take Hysingla ER with water to swallow the tablets, 11 out of 2476 subjects reported difficulty swallowing Hysingla ER. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet. Instruct patients not to pre-soak, lick or otherwise wet Hysingla ER tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth.
  • Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen.
Risks of Use in Patients with Gastrointestinal Conditions
  • Hysingla ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The hydrocodone in Hysingla ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis.
Increased Risk of Seizures in Patients with Seizure Disorders
  • The hydrocodone in Hysingla ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hysingla ER therapy.
Withdrawal
  • Avoid the use of mixed agonist/antagonist analgesics (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hysingla ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing Hysingla ER, gradually taper the dosage. Do not abruptly discontinue Hysingla ER.
Risks of Driving and Operating Machinery
  • Hysingla ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14–16 hours (range 6–30 hours) after initial dosing of Hysingla ER. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hysingla ER and know how they will react to the medication.
ADVERSE REACTIONS
  • The most common adverse reactions (≥5%) reported by patients treated with Hysingla ER in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence.

Intended for healthcare professionals of the United States of America only.