Hysingla ER (hydrocodone bitartrate 20 mg) Dailymed

• 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)
• 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)
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (2.1). 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, 5)
• 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, 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. (2.1, 5.2)
• 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, 5.1, 5.2, 5.3)
• Instruct patients to swallow HYSINGLA ER intact, and not to crush, chew, or dissolve the tablets (risk of potentially fatal overdose). (2.1, 5.1)
• Instruct patients to take tablets one at a time, with enough water to ensure complete swallowing immediately after placing in the mouth (2.1, 5.13)
• For opioid-naïve patients, initiate with 20 mg tablets orally every 24 hours. (2.3)
• To convert to HYSINGLA ER from another opioid, follow the conversion instructions to obtain an estimated dose. (2.3)
• Dose titration of HYSINGLA ER may occur every 3 to 5 days (2.4)
• 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)
• 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)
• 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)

2.1Important 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.

2.2Patient 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.

2.3Initial 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 uled 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.

2.4Titration 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.

2.5Dosage 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)].

2.6Dosage 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)].

2.7Safe 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 reaulic. 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 speciaul.

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)].

3dosage Forms And Strengths

• 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")

Extended-release tablets: 20, 30, 40, 60, 80, 100, and 120 mg (3)

4contraindications

HYSINGLA ER is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.8)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13, 5.14)]
• Hypersensitivity to hydrocodone or any component of HYSINGLA ER.

• Significant respiratory depression (4)
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (4)
• Known or suspected gastrointestinal obstruction, including paralytic ileus (4)
• Hypersensitivity to hydrocodone or to any other components of HYSINGLA ER (4)

5warnings 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. (5.7)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. (5.8)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.9)
• Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of HYSINGLA ER in patients with circulatory shock. (5.10)
• QTc Prolongation: Avoid use in patients with congenital long QTc syndrome. In patients who develop QTc prolongation, consider reducing the dose. (5.11, 12.2)
• 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. (5.12)
• 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. (5.14)

5.1Addiction, 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.

5.2Life-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)].

5.3Risks 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)].

5.4Neonatal 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)].

5.5Opioid 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 ul 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

5.6Risks 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)].

5.7Opioid-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)].

5.8Life-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.

5.9Adrenal 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.

5.10Severe 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.

5.11QTc 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.

5.12Risks 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.

5.13Gastrointestinal 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)].

5.14Risks 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.

5.15Increased 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.

5.16Withdrawal

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)].

5.17Risks 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.