Hysingla Er (Hydrocodone Bitartrate)

Check Drug InteractionsCheck known drug interactions.

Dosage & administration

* HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

* Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
*

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse

[see Warnings and Precautions (5.1)]

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments

[see Warnings and Precautions (5.2)].

* Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

)
* Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established.
* Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

)
* Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

). Reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using higher dose opioid clearly outweigh the substantial risks. (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

5 WARNINGS AND PRECAUTIONS

Opioid-Induced Hyperalgesia and Allodynia:

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
*

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patient

s: Regularly evaluate, particularly during initiation and titration.
*

Adrenal Insufficiency

: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
*

Severe Hypotension

: Regularly evaluate during dosage initiation and titration. Avoid use of HYSINGLA ER in patients with circulatory shock.
*

QTc Prolongation:

Avoid use in patients with congenital long QTc syndrome. In patients who develop QTc prolongation, consider reducing the dose.
*

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

: Monitor for sedation and respiratory depression. Avoid use of HYSINGLA ER in patients with circulatory shock.
*

Risk of Obstruction in Patients who have Difficulty Swallowing or have Underlying GI Disorders that may Predispose them to Obstruction

: Consider use of an alternative analgesic.

5.1 Addiction, Abuse, and Misuse

HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of 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

[see Drug Abuse and Dependence (9)]

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 reassess 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 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 frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

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

[see Drug Abuse and Dependence (9.2), Overdosage (10)]

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status

[see Overdosage (10)]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

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.

To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential

[see Dosage and Administration (2.1, 2.3)]

. 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.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper

[see Dosage and Administration (2.4)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone

[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

5.3 Risks of Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of HYSINGLA ER with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics

[see Drug Interactions (7)]

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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

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

[see Drug Interactions (7)].

5.4 Neonatal Opioid Withdrawal Syndrome

Use of HYSINGLA ER for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

[see Use in Specific Populations (8.1)].

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

* Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
* Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
* Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
* Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint

5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of HYSINGLA ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression

[see Warnings and Precautions (5.2)]

, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in HYSINGLA ER treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using HYSINGLA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in HYSINGLA ER-treated patients, evaluate patients at frequent intervals and consider dosage reduction of HYSINGLA ER until stable drug effects are achieved

[see Drug Interactions (7)].

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. When using HYSINGLA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, 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

[see Drug Interactions (7)].

5.7 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect

[see Dependence (9.3)]

. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety)

[see Dosage and Administration (2.7), Warnings and Precautions (5.16)].

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in 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.

Patients with Chronic Pulmonary Disease:

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

[see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients:

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

[see Warnings and Precautions (5.3)].

Regularly evaluate patients, particularly when initiating and titrating HYSINGLA ER and when HYSINGLA ER is given concomitantly with other drugs that depress respiration

[see Warnings and Precautions (5.2, 5.3),

Drug Interactions (7)

]

. Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. 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. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 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)

[see Drug Interactions (7)]

. Regularly evaluate 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.

5.11 QTc Interval Prolongation

QTc prolongation has been observed with HYSINGLA ER following daily doses of 160 mg

[see Clinical Pharmacology (12.2)]

. 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 the 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.

5.12 Risks 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 such patients for signs of sedation and respiratory depression, particularly when initiating therapy with HYSINGLA ER.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of HYSINGLA ER in patients with impaired consciousness or coma.

5.13 Gastrointestinal Obstruction, Dysphagia, and Choking

In the clinical studies with specific instructions to take HYSINGLA ER with adequate water to swallow the tablet, 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

[see Adverse Reactions (6)].

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.

Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER

[see Use in Specific Populations (8.4)]

5.14 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 serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.15 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during HYSINGLA ER therapy.

5.16 Withdrawal

Do not abruptly discontinue HYSINGLA ER in a patient physically dependent on opioids. When discontinuing HYSINGLA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

[see Dosage and Administration (2.7), Drug Abuse and Dependence (9.3)].

Additionally, 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

[see Drug Interactions (7)]

5.17 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 tablet administration. 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.

)
* Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

5.1 Addiction, Abuse, and Misuse

[see Drug Abuse and Dependence (9)]

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

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

[see Drug Abuse and Dependence (9.2), Overdosage (10)]

)
* Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments. (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential

[see Dosage and Administration (2.1, 2.3)]

. 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.

[see Dosage and Administration (2.4)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:

[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

)
* Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Consider prescribing naloxone based on the patient's risk factors for overdose (

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

[see Warnings and Precautions (5.2)].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

[see Warnings and Precautions (5.1, 5.2, 5.3)].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

5.1 Addiction, Abuse, and Misuse

[see Drug Abuse and Dependence (9)]

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

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

[see Drug Abuse and Dependence (9.2), Overdosage (10)]

5.2 Life-Threatening Respiratory Depression

[see Overdosage (10)]

. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential

[see Dosage and Administration (2.1, 2.3)]

. 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.

[see Dosage and Administration (2.4)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:

[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

5.3 Risks of Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions (7)]

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

[see Drug Interactions (7)].

)
* Instruct patients to swallow HYSINGLA ER intact, and not to crush, chew, or dissolve the tablets (risk of potentially fatal overdose). (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

5.1 Addiction, Abuse, and Misuse

[see Drug Abuse and Dependence (9)]

[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

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

[see Drug Abuse and Dependence (9.2), Overdosage (10)]

)
* Instruct patients to take tablets one at a time, with enough water to ensure complete swallowing immediately after placing in the mouth (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals

[see Warnings and Precautions (5)]

[see Warnings and Precautions (5.1)]

[see Warnings and Precautions (5.2)].

[see Warnings and Precautions (5.13)].

Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death

[see Warnings and Precautions (5.1)]

.
* HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

5.13 Gastrointestinal Obstruction, Dysphagia, and Choking

[see Adverse Reactions (6)].

Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER

[see Use in Specific Populations (8.4)]

)
* For opioid-naïve patients, initiate with 20 mg tablets orally every 24 hours. (

2.3 Initial Dosage

Use of HYSINGLA ER as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with HYSINGLA ER at a dose of 20 mg orally every 24 hours.

Use of HYSINGLA ER in Patients who are not Opioid Tolerant

(opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is HYSINGLA ER 20 mg orally every 24 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Oral Hydrocodone Formulations to HYSINGLA ER

Patients receiving other oral hydrocodone-containing formulations may be converted to HYSINGLA ER by administering the patient's total daily oral hydrocodone dose as HYSINGLA ER once daily.

Conversion from Other Opioids to HYSINGLA ER

When HYSINGLA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There is inter-patient variability in the relative potency of opioid drugs and formulations. Therefore, a conservative approach is advised when determining the total daily dosage of HYSINGLA ER. It is safer to underestimate a patient's 24-hour oral hydrocodone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydrocodone dosage and manage an adverse reaction due to an overdose.

In a HYSINGLA ER clinical trial with an open-label titration period, patients were converted from their prior opioid to HYSINGLA ER using Table 1 as a guide for the initial HYSINGLA ER dose. To obtain the initial HYSINGLA ER dose, first use Table 1 to convert the prior oral opioids to a total hydrocodone daily dose and then reduce the calculated daily hydrocodone dose by 25% to account for interpatient variability in relative potency of different opioids.

Consider the following when using the information found in Table 1.

* This is

not

a table of equianalgesic doses.
* The conversion factors in this table are only for the conversion

from

one of the listed oral opioid analgesics to HYSINGLA ER.
* The table

cannot

be used to convert

from

HYSINGLA ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose

Table 1. Conversion factors to HYSINGLA ER (Not Equianalgesic Doses)
Opioid	Oral dose (mg)	Approximate oral conversion factor
Codeine	133	0.15
Hydromorphone	5	4
Methadone	13.3	1.5
Morphine	40	0.5
Oxycodone	20	1
Oxymorphone	10	2
Tramadol	200	0.1

To calculate the estimated total hydrocodone daily dose using Table 1:

* For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose.
* For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain the approximate oral hydrocodone daily dose.
* For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
* Reduce the calculated daily oral hydrocodone dose by 25%

Always round the dose down, if necessary, to the nearest HYSINGLA ER tablet strength available and initiate therapy with that dose. If the converted HYSINGLA ER dose using Table 1 is less than 20 mg, initiate therapy with HYSINGLA ER 20 mg.

Example conversion from a single opioid to HYSINGLA ER:

For example, a total daily dose of oxycodone 50 mg would be converted to hydrocodone 50 mg based on the table above, and then multiplied by 0.75 (i.e., take a 25 % reduction) resulting in a dose of 37.5 mg hydrocodone. Round this down to the nearest dose strength available, HYSINGLA ER 30 mg, to initiate therapy.

Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to HYSINGLA ER.

Conversion from Methadone to HYSINGLA ER

Regular evaluation is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Conversion from Transdermal Fentanyl to HYSINGLA ER

Eighteen hours following the removal of the transdermal fentanyl patch, HYSINGLA ER treatment can be initiated. For each 25 mcg/hr fentanyl transdermal patch, a dose of HYSINGLA ER 20 mg every 24 hours represents a conservative initial dose. Follow the patient closely during conversion from transdermal fentanyl to HYSINGLA ER, as there is limited experience with this conversion.

Conversion from Transdermal Buprenorphine to HYSINGLA ER

All patients receiving transdermal buprenorphine (≤ 20 mcg/hr) should initiate therapy with HYSINGLA ER 20 mg every 24 hours. Follow the patient closely during conversion from transdermal buprenorphine to HYSINGLA ER, as there is limited experience with this conversion.

)
* To convert to HYSINGLA ER from another opioid, follow the conversion instructions to obtain an estimated dose. (

2.3 Initial Dosage

Use of HYSINGLA ER as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with HYSINGLA ER at a dose of 20 mg orally every 24 hours.

Use of HYSINGLA ER in Patients who are not Opioid Tolerant

(opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is HYSINGLA ER 20 mg orally every 24 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Oral Hydrocodone Formulations to HYSINGLA ER

Patients receiving other oral hydrocodone-containing formulations may be converted to HYSINGLA ER by administering the patient's total daily oral hydrocodone dose as HYSINGLA ER once daily.

Conversion from Other Opioids to HYSINGLA ER

When HYSINGLA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

Consider the following when using the information found in Table 1.

* This is

not

a table of equianalgesic doses.
* The conversion factors in this table are only for the conversion

from

one of the listed oral opioid analgesics to HYSINGLA ER.
* The table

cannot

be used to convert

from

HYSINGLA ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose

Table 1. Conversion factors to HYSINGLA ER (Not Equianalgesic Doses)
Opioid	Oral dose (mg)	Approximate oral conversion factor
Codeine	133	0.15
Hydromorphone	5	4
Methadone	13.3	1.5
Morphine	40	0.5
Oxycodone	20	1
Oxymorphone	10	2
Tramadol	200	0.1

To calculate the estimated total hydrocodone daily dose using Table 1:

Example conversion from a single opioid to HYSINGLA ER:

Conversion from Methadone to HYSINGLA ER

Conversion from Transdermal Fentanyl to HYSINGLA ER

Conversion from Transdermal Buprenorphine to HYSINGLA ER

)
* Dose titration of HYSINGLA ER may occur every 3 to 5 days (

2.4 Titration and Maintenance of Therapy

Individually titrate HYSINGLA ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving HYSINGLA ER to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other relative incidence of adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse

[see Warnings and Precautions (5.1, 5.16)]

. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.

Patients who experience breakthrough pain may require a dosage adjustment of HYSINGLA ER, or may need rescue medication with an appropriate dose of an immediate-release analgesic.

If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the HYSINGLA ER dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage

[see Warnings and Precautions (5)].

Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Adjust the dose of HYSINGLA ER in increments of 10 mg to 20 mg every 3 to 5 days as needed to achieve adequate analgesia.

)
*

Patients with Severe Hepatic Impairment

: Initiate dosing with one half of the recommended starting dosage and titrate carefully. Regularly evaluate for respiratory depression, sedation, and hypotension. (

2.5 Dosage Modifications in Patients with Severe Hepatic Impairment

Patients with severe hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function. Initiate therapy with one half the initial dose of HYSINGLA ER in these patients and regularly evaluate for respiratory depression, sedation, and hypotension

[see Clinical Pharmacology (12.3)]

)
*

Patients with Moderate to Severe Renal Impairment and End-Stage Renal Disease

: Initiate dosing at one half the recommended starting dosage and titrate carefully. Regularly evaluate for signs of respiratory depression, sedation, and hypotension. (

2.6 Dosage Modifications in Patients with Moderate to Severe Renal Impairment

Patients with moderate to severe renal impairment, and end-stage renal disease may have higher plasma concentrations than those with normal function. Initiate therapy with one half the initial dose of HYSINGLA ER in these patients and regularly evaluate for respiratory depression, sedation, and hypotension

[see Clinical Pharmacology (12.3)]

)
* Do not abruptly discontinue HYSINGLA ER in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (

2.7 Safe Reduction or Discontinuation of HYSINGLA ER

Do not abruptly discontinue HYSINGLA ER in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking HYSINGLA ER, there are a variety of factors that should be considered, including the total daily dose opioid (including HYSINGLA ER) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on HYSINGLA ER who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic

[see Warnings and Precautions (5.16), Drug Abuse and Dependence (9.3)]

)

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Hysingla ER prescribing information

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYSINGLA ER

See full prescribing information for complete boxed warning.

HYSINGLA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing, and reassess regularly for these behaviors and conditions. (
5.1 Addiction, Abuse, and Misuse
HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of 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
[see Drug Abuse and Dependence (9)]
.
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 reassess 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 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 frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
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
[see Drug Abuse and Dependence (9.2), Overdosage (10)]
.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
)
Serious, life-threatening, or fatal respiratory depression may occur, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential. Instruct patients to swallow HYSINGLA ER whole to avoid exposure to a potentially fatal dose of hydrocodone. (
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status
[see Overdosage (10)]
. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
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.
To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential
[see Dosage and Administration (2.1, 2.3)]
. 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.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.4)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
)
Accidental ingestion of HYSINGLA ER, especially by children, can result in fatal overdose of hydrocodone. (
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status
[see Overdosage (10)]
. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
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.
To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential
[see Dosage and Administration (2.1, 2.3)]
. 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.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.4)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
)

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. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (

5.3 Risks of Concomitant Use with Benzodiazepines or Other CNS Depressants

[see Drug Interactions (7)]

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

[see Drug Interactions (7)].

7 DRUG INTERACTIONS

Table 3 includes clinically significant drug interactions with HYSINGLA ER.

Table 3: Clinically Significant Drug Interactions with HYSINGLA ER
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of HYSINGLA ER and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of HYSINGLA ER and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved [see Warnings and Precautions (5.6)] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology (12.3)] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of HYSINGLA ER until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact:	The concomitant use of HYSINGLA ER and CYP3A4 inducers can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions (5.6)] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider HYSINGLA ER dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3)].
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.3)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome .
Intervention:	If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue HYSINGLA ER if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)] .
Intervention:	The use of HYSINGLA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of HYSINGLA ER and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Because respiratory depression may be greater than otherwise expected, decrease the dosage of HYSINGLA ER and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3)].
Example:	Cyclobenzaprine, metaxalone
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Evaluate patients for signs of urinary retention or reduced gastric motility when HYSINGLA ER is used concomitantly with anticholinergic drugs.
Strong Laxatives
Clinical Impact:	Concomitant use of HYSINGLA ER with strong laxatives that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels.
Intervention:	If HYSINGLA ER is used in these patients, regularly evaluate for the development of adverse events as well as changing analgesic requirements.
Example:	lactulose

Serotonergic Drugs
: Concomitant use may result in serotonin syndrome. Discontinue HYSINGLA ER if serotonin syndrome is suspected.
Mixed Agonists/Antagonists and Partial Agonist Opioid Analgesics: Avoid use with HYSINGLA ER because they may reduce analgesic effect of HYSINGLA ER or precipitate withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs)
: Can potentiate the effects of hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI.

)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery (
5.4 Neonatal Opioid Withdrawal Syndrome
Use of HYSINGLA ER for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
[see Use in Specific Populations (8.1)].
)
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (
5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint
)

Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone. (

5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

[see Warnings and Precautions (5.2)]

[see Drug Interactions (7)].

7 DRUG INTERACTIONS

Table 3 includes clinically significant drug interactions with HYSINGLA ER.

Table 3: Clinically Significant Drug Interactions with HYSINGLA ER
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of HYSINGLA ER and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of HYSINGLA ER and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved [see Warnings and Precautions (5.6)] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology (12.3)] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of HYSINGLA ER until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact:	The concomitant use of HYSINGLA ER and CYP3A4 inducers can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions (5.6)] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider HYSINGLA ER dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3)].
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.2, 5.3)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome .
Intervention:	If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue HYSINGLA ER if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)] .
Intervention:	The use of HYSINGLA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of HYSINGLA ER and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Because respiratory depression may be greater than otherwise expected, decrease the dosage of HYSINGLA ER and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3)].
Example:	Cyclobenzaprine, metaxalone
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Evaluate patients for signs of urinary retention or reduced gastric motility when HYSINGLA ER is used concomitantly with anticholinergic drugs.
Strong Laxatives
Clinical Impact:	Concomitant use of HYSINGLA ER with strong laxatives that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels.
Intervention:	If HYSINGLA ER is used in these patients, regularly evaluate for the development of adverse events as well as changing analgesic requirements.
Example:	lactulose

Serotonergic Drugs
: Concomitant use may result in serotonin syndrome. Discontinue HYSINGLA ER if serotonin syndrome is suspected.
Mixed Agonists/Antagonists and Partial Agonist Opioid Analgesics: Avoid use with HYSINGLA ER because they may reduce analgesic effect of HYSINGLA ER or precipitate withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs)
: Can potentiate the effects of hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI.

12.3 Pharmacokinetics

Absorption

HYSINGLA ER is a single-entity extended-release formulation of hydrocodone that yields a gradual increase in plasma hydrocodone concentrations with a median T_maxof 14 – 16 hours noted for different dose strengths. Peak plasma levels may occur in the range of 6 -30 hours after single dose HYSINGLA ER administration.

Systemic exposure (AUC and C_max) increased linearly with doses from 20 to 120 mg. Both C_maxand AUC increased slightly more than dose proportionally (Table 6). The mean terminal half-life (t_1/2) was similar for all HYSINGLA ER dose strengths ranging from 7 to 9 hours.

Table 6 Mean (SD) Single-Dose Pharmacokinetic Parameters of HYSINGLA ER
Dose Strength (mg)	AUCinf (ng∙h/mL)	C_max (ng/mL)	T_maxmedian (minimum, maximum) (h)
20	284 (128)	14.6 (5.5)	16 (6, 24)
40	622 (252)	33.9 (11.8)	16 (6, 24)
60	1009 (294)	53.6 (15.4)	14 (10, 30)
80	1304 (375)	69.1 (17.2)	16 (10, 24)
120	1787 (679)	110 (44.1)	14 (6, 30)

As compared to an immediate-release hydrocodone combination product, HYSINGLA ER at the same daily dose results in similar bioavailability but with lower maximum concentrations at steady state (Figure 3).

Figure 3. Mean Steady-State Plasma Hydrocodone Concentration Profile

Steady-state plasma hydrocodone concentrations were confirmed on day 3 of once-daily dosing of HYSINGLA ER. The extent of accumulation of systemic exposure was 1.3 and 1.1 fold with respect to AUC and C_maxat steady-state. The mean terminal half-life (t_1/2) at steady state was 7 hours. Median T_maxvalues were 14 hours (range: 12 to 24 hours) on both Day 1 and Day 5 following once daily administration of HYSINGLA ER for five days. Daily fluctuation in peak to trough plasma levels of hydrocodone were higher at 80 mg and 120 mg doses of HYSINGLA ER compared to 30 mg dose (Table 7).

Table 7 Mean (SD) Steady-State Hydrocodone Pharmacokinetic Parameters
Regimen	AUC24,ss (ng∙h/mL)	C_max,ss (ng/mL)	C_min,ss (ng/mL)	%FluctuationMean (minimum, maximum); Percentage fluctuation in plasma concentration is derived as (C_max,ss – C_min, ss)*100/Cavg,ss.
HYSINGLA ER
30 mg q24h	443 (128)	26.4 (7.4)	16.7 (5.2)	61 (6.4,113)
80 mg q24h	1252 (352)	82.6 (25.7)	28.2 (12)	105 (36,214)
120 mg q24h	1938 (729)	135 (50)	63.6 (29)	97.9 (32, 250)

Food Effects

C_maxand AUC of HYSINGLA ER 120 mg tablets were similar under low fat conditions relative to fasting conditions (17% and 9% higher, respectively). C_maxwas higher (54%) under high fat conditions relative to fasting conditions; however, AUC of HYSINGLA ER 120 mg tablets was only 20% higher when co-administered with a high fat meal. HYSINGLA ER may be administered without regard to meals.

Distribution

Following administration of HYSINGLA ER, the typical (70 kg adult) value of apparent volume of distribution (V/F) is 402 L, suggesting extensive tissue distribution. The extent of

in vivo

binding of hydrocodone to human plasma proteins was minimal with a mean % bound at 36%.

Elimination

Metabolism

Hydrocodone exhibits a complex pattern of metabolism, including

-demethylation,

-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated

-demethylation to inactive norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2B6 and CYP2C19. The minor metabolite hydromorphone (<3% of the circulating parent hydrocodone) was mainly formed by CYP2D6 mediated

-demethylation with a smaller contribution by CYP2B6 and CYP2C19. Hydromorphone may contribute to the total analgesic effect of hydrocodone.

Excretion

Hydrocodone and its metabolites are cleared primarily by renal excretion. The percent of administered dose excreted unchanged as hydrocodone in urine was 6.5% in subjects with normal renal function, and 5.0%, 4.8%, and 2.3% in subjects with mild, moderate, and severe renal impairment, respectively. Renal clearance (CLr) of hydrocodone in healthy subjects was small (5.3 L/h) compared to apparent oral clearance (CL/F, 83 L/h); suggesting that non-renal clearance is the main elimination route. Ninety-nine percent of the administered dose is eliminated within 72 hours. The mean terminal half-life (t_1/2) was similar for all HYSINGLA ER dose strengths ranging from approximately 7 to 9 hours across the range of doses.

Specific Populations

Age: Geriatric Patients

Following administration of 40 mg HYSINGLA ER, the pharmacokinetics of hydrocodone in healthy elderly subjects (65 to 77 years) are similar to the pharmacokinetics in healthy younger subjects (20 to 45 years). There were no clinically meaningful increase in C_max(16%) and AUC (15%) of hydrocodone in elderly as compared with younger adult subjects

[see Use in Specific Populations (8.5)]

Sex

Systemic exposure of hydrocodone (C_maxand AUC) was similar between males and females.

Hepatic Impairment

After a single dose of 20 mg HYSINGLA ER in subjects (8 each) with normal hepatic function, mild, moderate or severe hepatic impairment based on Child-Pugh classifications, mean hydrocodone C_maxvalues were 16, 15, 17, and 18 ng/mL, respectively. Mean hydrocodone AUC values were 342, 310, 390, and 415 ng.hr/mL for subjects with normal hepatic function, mild, moderate or severe hepatic impairment, respectively. Geometric mean hydrocodone C_maxvalues were -6%, 5%, and 5% and AUC values were -14%, 13%, and 4% in patients with mild, moderate or severe hepatic impairment, respectively, when compared with subjects with normal hepatic function.

The mean

in vivo

plasma protein binding of hydrocodone across the groups was similar, ranging from 33% to 37%

[see Use in Specific Populations (8.6)].

Renal Impairment

After a single dose of 60 mg HYSINGLA ER in subjects (8 each) with normal renal function, mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria and end stage renal disease (with dialysis) patients, mean hydrocodone C_maxvalues were 40, 50, 51, 46, and 38 ng/mL, respectively. Mean hydrocodone AUC values were 754, 942, 1222, 1220, and 932 ng.hr/mL for subjects with normal renal function, mild, moderate or severe renal impairment and ESRD with dialysis, respectively. Hydrocodone C_maxvalues were 14%, 23%, 11% and -13% and AUC values were 13%, 61%, 57% and 4% higher in patients with mild, moderate or severe renal impairment or end stage renal disease with dialysis, respectively

[see Use in Specific Populations (8.7)].

Drug Interaction Studies

CYP3A4

Co-administration of HYSINGLA ER (20 mg single dose) and CYP3A4 inhibitor ketoconazole (200 mg BID for 6 days) increased mean hydrocodone AUC and C_maxby 135% and 78%, respectively

[see Warnings and Precautions (5.6)and Drug Interactions (7)]

CYP2D6

The 90% confidence interval (CI) of the geometric means for hydrocodone AUC_inf(98 to 115%), AUC_t(98 to 115%), and C_max(93 to 121%) values were within the range of 80 to 125% when a single dose of HYSINGLA ER 20 mg was co-administered with CYP2D6 inhibitor paroxetine (20 mg treatment each morning for 12 days). No differences in systemic exposure of hydrocodone were observed in the presence of paroxetine.

)

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYSINGLA ER

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYSINGLA ER

See full prescribing information for complete boxed warning.

HYSINGLA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing, and reassess regularly for these behaviors and conditions.
Serious, life-threatening, or fatal respiratory depression may occur, especially upon initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential. Instruct patients to swallow HYSINGLA ER whole to avoid exposure to a potentially fatal dose of hydrocodone.
Accidental ingestion of HYSINGLA ER, especially by children, can result in fatal overdose of hydrocodone.
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. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate.
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.
Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone.

Addiction, Abuse, and Misuse

Because the use of 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 and reassess 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, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential. 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)]

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. Reserve concomitant prescribing of HYSINGLA ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate

[see Warnings and Precautions (5.3), Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery

[see Warnings and Precautions (5.4)]

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription

[see Warnings and Precautions (5.5)].

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. Regularly evaluate patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer

[see Warnings and Precautions (5.6), Drug Interactions (7), and Clinical Pharmacology (12.3)].

12/2023

Indications and Usage (

1 INDICATIONS AND USAGE

HYSINGLA ER is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

HYSINGLA ER is an opioid agonist indicated for the management of severe and persistent pain that requires an extended period with a daily opioid analgesic and for which alternative treatment options are inadequate.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting 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.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations
[see Warnings and Precautions (5.1)]
, 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.

)

12/2023

Dosage and Administration (

2.1 Important Dosage and Administration Instructions

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
[see Warnings and Precautions (5)]
. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
[see Warnings and Precautions (5.1)]
.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
[see Warnings and Precautions (5.2)].
Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
[see Warnings and Precautions (5.13)].
Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
[see Warnings and Precautions (5.1)]
.
HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.

2.3 Initial Dosage

Use of HYSINGLA ER as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with HYSINGLA ER at a dose of 20 mg orally every 24 hours.

Use of HYSINGLA ER in Patients who are not Opioid Tolerant

(opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is HYSINGLA ER 20 mg orally every 24 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Oral Hydrocodone Formulations to HYSINGLA ER

Patients receiving other oral hydrocodone-containing formulations may be converted to HYSINGLA ER by administering the patient's total daily oral hydrocodone dose as HYSINGLA ER once daily.

Conversion from Other Opioids to HYSINGLA ER

When HYSINGLA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

Consider the following when using the information found in Table 1.

This is
not
a table of equianalgesic doses.
The conversion factors in this table are only for the conversion
from
one of the listed oral opioid analgesics to HYSINGLA ER.
The table
cannot
be used to convert
from
HYSINGLA ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose

Table 1. Conversion factors to HYSINGLA ER (Not Equianalgesic Doses)
Opioid	Oral dose (mg)	Approximate oral conversion factor
Codeine	133	0.15
Hydromorphone	5	4
Methadone	13.3	1.5
Morphine	40	0.5
Oxycodone	20	1
Oxymorphone	10	2
Tramadol	200	0.1

To calculate the estimated total hydrocodone daily dose using Table 1:

For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose.
For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain the approximate oral hydrocodone daily dose.
For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Reduce the calculated daily oral hydrocodone dose by 25%

Example conversion from a single opioid to HYSINGLA ER:

Conversion from Methadone to HYSINGLA ER

Conversion from Transdermal Fentanyl to HYSINGLA ER

Conversion from Transdermal Buprenorphine to HYSINGLA ER

2.4 Titration and Maintenance of Therapy

[see Warnings and Precautions (5.1, 5.16)]

Patients who experience breakthrough pain may require a dosage adjustment of HYSINGLA ER, or may need rescue medication with an appropriate dose of an immediate-release analgesic.

[see Warnings and Precautions (5)].

)

12/2023

Warnings and Precautions (

5.7 Opioid-Induced Hyperalgesia and Allodynia

[see Dependence (9.3)]

[see Dosage and Administration (2.7), Warnings and Precautions (5.16)].

)

12/2023

HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
)
Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established.
Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
)
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
). Reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using higher dose opioid clearly outweigh the substantial risks. (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
,
5 WARNINGS AND PRECAUTIONS
Opioid-Induced Hyperalgesia and Allodynia:
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patient
s: Regularly evaluate, particularly during initiation and titration.
Adrenal Insufficiency
: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
Severe Hypotension
: Regularly evaluate during dosage initiation and titration. Avoid use of HYSINGLA ER in patients with circulatory shock.
QTc Prolongation:
Avoid use in patients with congenital long QTc syndrome. In patients who develop QTc prolongation, consider reducing the dose.
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
: Monitor for sedation and respiratory depression. Avoid use of HYSINGLA ER in patients with circulatory shock.
Risk of Obstruction in Patients who have Difficulty Swallowing or have Underlying GI Disorders that may Predispose them to Obstruction
: Consider use of an alternative analgesic.
5.1 Addiction, Abuse, and Misuse
HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of 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
[see Drug Abuse and Dependence (9)]
.
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 reassess 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 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 frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
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
[see Drug Abuse and Dependence (9.2), Overdosage (10)]
.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status
[see Overdosage (10)]
. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
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.
To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential
[see Dosage and Administration (2.1, 2.3)]
. 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.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.4)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
5.3 Risks of Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of HYSINGLA ER with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics
[see Drug Interactions (7)]
.
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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].
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
[see Drug Interactions (7)].
5.4 Neonatal Opioid Withdrawal Syndrome
Use of HYSINGLA ER for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
[see Use in Specific Populations (8.1)].
5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint
5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
Concomitant use of HYSINGLA ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression
[see Warnings and Precautions (5.2)]
, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in HYSINGLA ER treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When using HYSINGLA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in HYSINGLA ER-treated patients, evaluate patients at frequent intervals and consider dosage reduction of HYSINGLA ER until stable drug effects are achieved
[see Drug Interactions (7)].
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. When using HYSINGLA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, 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
[see Drug Interactions (7)].
5.7 Opioid-Induced Hyperalgesia and Allodynia
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect
[see Dependence (9.3)]
. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety)
[see Dosage and Administration (2.7), Warnings and Precautions (5.16)].
5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in 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.
Patients with Chronic Pulmonary Disease:
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
[see Warnings and Precautions (5.2)].
Elderly, Cachectic, or Debilitated Patients:
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
[see Warnings and Precautions (5.3)].
Regularly evaluate patients, particularly when initiating and titrating HYSINGLA ER and when HYSINGLA ER is given concomitantly with other drugs that depress respiration
[see Warnings and Precautions (5.2, 5.3),
Drug Interactions (7)
]
. Alternatively, consider the use of non-opioid analgesics in these patients.
5.9 Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. 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. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
5.10 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)
[see Drug Interactions (7)]
. Regularly evaluate 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.
5.11 QTc Interval Prolongation
QTc prolongation has been observed with HYSINGLA ER following daily doses of 160 mg
[see Clinical Pharmacology (12.2)]
. 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 the 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.
5.12 Risks 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 such patients for signs of sedation and respiratory depression, particularly when initiating therapy with HYSINGLA ER.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of HYSINGLA ER in patients with impaired consciousness or coma.
5.13 Gastrointestinal Obstruction, Dysphagia, and Choking
In the clinical studies with specific instructions to take HYSINGLA ER with adequate water to swallow the tablet, 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
[see Adverse Reactions (6)].
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.
Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER
[see Use in Specific Populations (8.4)]
.
5.14 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 serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
5.15 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during HYSINGLA ER therapy.
5.16 Withdrawal
Do not abruptly discontinue HYSINGLA ER in a patient physically dependent on opioids. When discontinuing HYSINGLA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
[see Dosage and Administration (2.7), Drug Abuse and Dependence (9.3)].
Additionally, 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
[see Drug Interactions (7)]
.
5.17 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 tablet administration. 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.
)
Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
,
5.1 Addiction, Abuse, and Misuse
HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of 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
[see Drug Abuse and Dependence (9)]
.
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 reassess 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 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 frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
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
[see Drug Abuse and Dependence (9.2), Overdosage (10)]
.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
)
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments. (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
,
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status
[see Overdosage (10)]
. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
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.
To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential
[see Dosage and Administration (2.1, 2.3)]
. 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.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.4)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
)
Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Consider prescribing naloxone based on the patient's risk factors for overdose (
2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER
[see Warnings and Precautions (5.2)].
Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient
[see Warnings and Precautions (5.1, 5.2, 5.3)].
Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.
,
5.1 Addiction, Abuse, and Misuse
HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of 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
[see Drug Abuse and Dependence (9)]
.
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 reassess 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 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 frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
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
[see Drug Abuse and Dependence (9.2), Overdosage (10)]
.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
,
5.2 Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status
[see Overdosage (10)]
. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
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.
To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential
[see Dosage and Administration (2.1, 2.3)]
. 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.
Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
[see Dosage and Administration (2.4)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose:
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with HYSINGLA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered.
Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone
[see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].
,
5.3 Risks of Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of HYSINGLA ER with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics
[see Drug Interactions (7)]
.
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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].
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
[see Drug Interactions (7)].
)
Instruct patients to swallow HYSINGLA ER intact, and not to crush, chew, or dissolve the tablets (risk of potentially fatal overdose). (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
,
5.1 Addiction, Abuse, and Misuse
HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of 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
[see Drug Abuse and Dependence (9)]
.
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 reassess 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 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 frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose
[see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
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
[see Drug Abuse and Dependence (9.2), Overdosage (10)]
.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
)
Instruct patients to take tablets one at a time, with enough water to ensure complete swallowing immediately after placing in the mouth (
2.1 Important Dosage and Administration Instructions
- HYSINGLA ER should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.
- Daily doses of HYSINGLA ER greater than or equal to 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
- Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
  [see Warnings and Precautions (5)]
  . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of HYSINGLA ER for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
- Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
  [see Warnings and Precautions (5.1)]
  .
- Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with HYSINGLA ER. Consider this risk when selecting an initial dose and when making dose adjustments
  [see Warnings and Precautions (5.2)].
- Instruct patients to swallow HYSINGLA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth
  [see Warnings and Precautions (5.13)].
  Crushing, chewing, or dissolving HYSINGLA ER tablets will result in uncontrolled delivery of hydrocodone and can lead to overdose or death
  [see Warnings and Precautions (5.1)]
  .
- HYSINGLA ER is administered orally once daily (every 24 hours). Multiple tablets of lower dose strengths that provide the desired total daily dose can be taken as a once daily dose.
,
5.13 Gastrointestinal Obstruction, Dysphagia, and Choking
In the clinical studies with specific instructions to take HYSINGLA ER with adequate water to swallow the tablet, 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
[see Adverse Reactions (6)].
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.
Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER
[see Use in Specific Populations (8.4)]
.
)

For opioid-naïve patients, initiate with 20 mg tablets orally every 24 hours. (

2.3 Initial Dosage

Use of HYSINGLA ER as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with HYSINGLA ER at a dose of 20 mg orally every 24 hours.

Use of HYSINGLA ER in Patients who are not Opioid Tolerant

(opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is HYSINGLA ER 20 mg orally every 24 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Oral Hydrocodone Formulations to HYSINGLA ER

Patients receiving other oral hydrocodone-containing formulations may be converted to HYSINGLA ER by administering the patient's total daily oral hydrocodone dose as HYSINGLA ER once daily.

Conversion from Other Opioids to HYSINGLA ER

When HYSINGLA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

Consider the following when using the information found in Table 1.

This is
not
a table of equianalgesic doses.
The conversion factors in this table are only for the conversion
from
one of the listed oral opioid analgesics to HYSINGLA ER.
The table
cannot
be used to convert
from
HYSINGLA ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose

Table 1. Conversion factors to HYSINGLA ER (Not Equianalgesic Doses)
Opioid	Oral dose (mg)	Approximate oral conversion factor
Codeine	133	0.15
Hydromorphone	5	4
Methadone	13.3	1.5
Morphine	40	0.5
Oxycodone	20	1
Oxymorphone	10	2
Tramadol	200	0.1

To calculate the estimated total hydrocodone daily dose using Table 1:

For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose.
For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain the approximate oral hydrocodone daily dose.
For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Reduce the calculated daily oral hydrocodone dose by 25%

Example conversion from a single opioid to HYSINGLA ER:

Conversion from Methadone to HYSINGLA ER

Conversion from Transdermal Fentanyl to HYSINGLA ER

Conversion from Transdermal Buprenorphine to HYSINGLA ER

)

To convert to HYSINGLA ER from another opioid, follow the conversion instructions to obtain an estimated dose. (

2.3 Initial Dosage

Use of HYSINGLA ER as the First Opioid Analgesic (opioid-naïve patients)

Initiate treatment with HYSINGLA ER at a dose of 20 mg orally every 24 hours.

Use of HYSINGLA ER in Patients who are not Opioid Tolerant

(opioid non-tolerant patients)

The starting dose for patients who are not opioid tolerant is HYSINGLA ER 20 mg orally every 24 hours.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression

[see Warnings and Precautions (5.2)]

Conversion from Oral Hydrocodone Formulations to HYSINGLA ER

Patients receiving other oral hydrocodone-containing formulations may be converted to HYSINGLA ER by administering the patient's total daily oral hydrocodone dose as HYSINGLA ER once daily.

Conversion from Other Opioids to HYSINGLA ER

When HYSINGLA ER therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

Consider the following when using the information found in Table 1.

This is
not
a table of equianalgesic doses.
The conversion factors in this table are only for the conversion
from
one of the listed oral opioid analgesics to HYSINGLA ER.
The table
cannot
be used to convert
from
HYSINGLA ER to another opioid. Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose

Table 1. Conversion factors to HYSINGLA ER (Not Equianalgesic Doses)
Opioid	Oral dose (mg)	Approximate oral conversion factor
Codeine	133	0.15
Hydromorphone	5	4
Methadone	13.3	1.5
Morphine	40	0.5
Oxycodone	20	1
Oxymorphone	10	2
Tramadol	200	0.1

To calculate the estimated total hydrocodone daily dose using Table 1:

For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose.
For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain the approximate oral hydrocodone daily dose.
For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Reduce the calculated daily oral hydrocodone dose by 25%

Example conversion from a single opioid to HYSINGLA ER:

Conversion from Methadone to HYSINGLA ER

Conversion from Transdermal Fentanyl to HYSINGLA ER

Conversion from Transdermal Buprenorphine to HYSINGLA ER

)

Dose titration of HYSINGLA ER may occur every 3 to 5 days (
2.4 Titration and Maintenance of Therapy
Individually titrate HYSINGLA ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving HYSINGLA ER to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other relative incidence of adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse
[see Warnings and Precautions (5.1, 5.16)]
. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for the use of opioid analgesics.
Patients who experience breakthrough pain may require a dosage adjustment of HYSINGLA ER, or may need rescue medication with an appropriate dose of an immediate-release analgesic.
If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the HYSINGLA ER dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage
[see Warnings and Precautions (5)].
Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. Adjust the dose of HYSINGLA ER in increments of 10 mg to 20 mg every 3 to 5 days as needed to achieve adequate analgesia.
)
Patients with Severe Hepatic Impairment
: Initiate dosing with one half of the recommended starting dosage and titrate carefully. Regularly evaluate for respiratory depression, sedation, and hypotension. (
2.5 Dosage Modifications in Patients with Severe Hepatic Impairment
Patients with severe hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function. Initiate therapy with one half the initial dose of HYSINGLA ER in these patients and regularly evaluate for respiratory depression, sedation, and hypotension
[see Clinical Pharmacology (12.3)]
.
)
Patients with Moderate to Severe Renal Impairment and End-Stage Renal Disease
: Initiate dosing at one half the recommended starting dosage and titrate carefully. Regularly evaluate for signs of respiratory depression, sedation, and hypotension. (
2.6 Dosage Modifications in Patients with Moderate to Severe Renal Impairment
Patients with moderate to severe renal impairment, and end-stage renal disease may have higher plasma concentrations than those with normal function. Initiate therapy with one half the initial dose of HYSINGLA ER in these patients and regularly evaluate for respiratory depression, sedation, and hypotension
[see Clinical Pharmacology (12.3)]
.
)
Do not abruptly discontinue HYSINGLA ER in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
2.7 Safe Reduction or Discontinuation of HYSINGLA ER
Do not abruptly discontinue HYSINGLA ER in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking HYSINGLA ER, there are a variety of factors that should be considered, including the total daily dose opioid (including HYSINGLA ER) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on HYSINGLA ER who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic
[see Warnings and Precautions (5.16), Drug Abuse and Dependence (9.3)]
.
)

20 mg film-coated extended-release tablets (round, green-colored, bi-convex tablets printed with "HYD 20")
30 mg film-coated extended-release tablets (round, yellow-colored, bi-convex tablets printed with "HYD 30")
40 mg film-coated extended-release tablets (round, grey-colored, bi-convex tablets printed with "HYD 40")
60 mg film-coated extended-release tablets (round, beige-colored, bi-convex tablets printed with "HYD 60")
80 mg film-coated extended-release tablets (round, pink-colored, bi-convex tablets printed with "HYD 80")
100 mg film-coated extended-release tablets (round, blue-colored, bi-convex tablets printed with "HYD 100")
120 mg film-coated extended-release tablets (round, white-colored, bi-convex tablets printed with "HYD 120")

Pregnancy
: May cause fetal harm. (
8.1 Pregnancy
Risk Summary
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome
[see Warnings and Precautions (5.4)]
. Available data with HYSINGLA ER in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies with hydrocodone in rats and rabbits no embryotoxicity or teratogenicity was observed. However, reduced pup survival rates, reduced fetal/pup body weights, and delayed ossification were observed at doses causing maternal toxicity. In all of the studies conducted, the exposures in animals were less than the human exposure
[see Data]
.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/neonatal adverse reactions
Use of opioid analgesics for extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly
[see Warnings and Precautions (5.4)]
.
Labor and Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. HYSINGLA ER is not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including HYSINGLA ER, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Data
Animal Data
No evidence of embryotoxicity or teratogenicity was observed after oral administration of hydrocodone throughout the period of organogenesis in rats and rabbits at doses up to 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). However, in these studies, reduced fetal body weights and delayed ossification were observed in rat at 30 mg/kg/day and reduced fetal body weights were observed in rabbits at 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a pre- and post-natal development study pregnant rats were administered oral hydrocodone throughout the period of gestation and lactation. At a dose of 30 mg/kg/day decreased pup viability, pup survival indices, litter size and pup body weight were observed. This dose is approximately 0.1 times the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons.
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Lactation
: Not recommended. (
8.2 Lactation
Risk Summary
Hydrocodone is present in human milk. A published lactation study reports variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period. This lactation study did not assess breastfed infants for potential adverse drug reactions. Lactation studies have not been conducted with HYSINGLA, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with HYSINGLA ER.
Clinical Considerations
Monitor infants exposed to HYSINGLA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.
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Hysingla Er (Hydrocodone Bitartrate)

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