Important Dosage and Administration Information

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

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 consistent with individual patient treatment goals [see Warnings and Precautions (5)].
• Initiate the dosing regimen for each patient individually; taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with HYSINGLA ER and adjust the dosage accordingly [see Warnings and Precautions (5.3)].

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 [see Patient Counseling Information (17)]. Instruct patients not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth [see Warnings and Precautions (5.12)]. 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.

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 (5.3), Patient Counseling Information (17)].

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, 5.3, 5.6)].

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

Initial Dosage

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

Initiate therapy with HYSINGLA ER 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 (5.3)].

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 Oral Opioids to HYSINGLA ER
Discontinue all other around-the-clock opioid drugs when HYSINGLA ER therapy is initiated.

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

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
Close monitoring 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.

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 and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1). 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 chronic therapy, 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. 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.

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

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 monitor closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

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 monitor closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

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 dose of 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, monitor 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 a long duration 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 (5.15), Drug Abuse and Dependence (9.3)].