Usual Adult Dose for Chronic Pain

The following dosing recommendations can only be considered suggested approaches to what is actually a series of clinical decisions over time; each patient should be managed individually.

As First Opioid Analgesic and For Patients who are NOT Opioid Tolerant:
Extended-Release Capsules (Zohydro(R) ER): Initial dose: 10 mg orally every 12 hours
Extended-Release Tablets (Hysingla(R) ER): Initial dose: 20 mg orally every 24 hours

Comments:

• Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression; monitor patients closely for respiratory depression, especially during the first 24 to 72 hours.
• An opioid tolerant patient is one who has been receiving for 1-week or longer at least: oral morphine 60 mg/day, fentanyl transdermal patch 25 mcg per hour, oral oxycodone 30 mg/day, oral hydromorphone 8 mg/day, oral oxymorphone 25 mg/day, or an equianalgesic dose of another opioid.

TITRATION AND MAINTENANCE:
Individually titrate to a dose that provides adequate analgesia and minimizes adverse reactions.

• Dose adjustments to hydrocodone extended-release capsules should be made in 10 mg increments every 12 hours, every 3 to 7 days.
• Dose adjustments to hydrocodone extended-release tablets should be made in 10 to 20 mg increments every 24 hours, every 3 to 5 days.
• If unacceptable side effects occur, the dose may be reduced.

Breakthrough Pain: If the level of pain increases after dose stabilization, attempt to identify the source before increasing dose; rescue medication with appropriate immediate-release analgesia may be helpful

DOSE CONVERSIONS: Dose conversions should be done carefully and with close monitoring due to large patient variability in regards to opioid analgesic response. Discontinue all other around the clock opioid drugs when initiating therapy with extended-release hydrocodone.

Hydrocodone Extended-Release (ER) CAPSULES:

• The 50 mg capsules, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are reserved for opioid tolerant individuals.

CONVERSION FROM OTHER ORAL OPIOIDS:

• Published potency tables can be used to estimate a patient's 24-hour oral hydrocodone requirement; however, due to substantial inter-patient variability, it is best to underestimate a patient's 24-hour requirement and provide rescue medication as the dose is titrated.
• Alternatively, the following conversion factors (CF) may be used to convert selected oral opioids to the hydrocodone extended-release capsule: Hydrocodone, CF=1; Oxycodone, CF=1; Methadone, CF= 1, Oxymorphone, CF=2; Hydromorphone, CF=2.67; Morphine, CF=0.67; Codeine, CF=0.1.
• These CFs cannot be used to convert from hydrocodone extended-release to the selected oral opioid as doing so will result in overestimation of the oral opioid dose and may result in fatal respiratory depression.
• Example: Sum the total daily dose of prior oral opioid; multiply that sum by the CF to obtain 24-hour oral hydrocodone requirement; divide 24-hour requirement by 2 (round down, if necessary ) and give 1 dose orally every 12 hours.

CONVERSION FROM TRANSDERMAL FENTANYL: Remove the transdermal fentanyl patch and 18 hours later initiate hydrocodone extended-release capsules at 10 mg every 12 hours for each 25 mcg/hr fentanyl transdermal patch; monitor closely as there is limited documented experience with this conversion.

Hydrocodone Extended-Release (ER) TABLETS:

• Daily dose greater than or equal to 80 mg are reserved for use in opioid tolerant individuals.
• CONVERSION FROM ORAL HYDROCODONE FORMULATIONS: Administer patient's total daily oral hydrocodone dose as extended-release tablet orally once a day.
• CONVERSION FROM OTHER ORAL OPIOIDS:
• Published potency tables can be used to estimate a patient's 24-hour oral hydrocodone requirement; however, due to substantial inter-patient variability, it is best to underestimate a patient's 24-hour requirement and provide rescue medication as the dose is titrated.
• To obtain the initial hydrocodone extended-release tablet dose, use the following conversion factors (CF) to convert selected oral opioids and then reduce that dose by 25%. Tramadol, CF=0.1; Oxycodone, CF=1; Methadone, CF= 1.5, Oxymorphone, CF=2; Hydromorphone, CF=4; Morphine, CF=0.5; Codeine, CF=0.15.
• These CFs cannot be used to convert from hydrocodone extended-release to the selected oral opioid as doing so will result in overestimation of the oral opioid dose and may result in fatal respiratory depression.
• Example: Sum the total daily dose of prior oral opioid; multiply that sum by the CF to obtain 24-hour oral hydrocodone requirement; reduce that hydrocodone requirement by 25% to account for interpatient variability, round down, if necessary; administer calculated dose orally once a day.

CONVERSION FROM TRANSDERMAL FENTANYL: Remove the transdermal fentanyl patch and 18 hours later initiate hydrocodone extended-release tablets at 20 mg every 24 hours for each 25 mcg/hr fentanyl transdermal patch; monitor closely as there is limited documented experience with this conversion.
CONVERSION FROM TRANSDERMAL BUPRENORPHINE: Patients receiving transdermal buprenorphine 20 mcg/hr or less should initiate extended-release hydrocodone tablets at 20 mg every 24 hours; monitor closely as there is limited documented experience with this conversion.

Comments:

• When converting from methadone, close monitoring is of particular importance due to methadone's long half-life.

Use: For the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Renal Dose Adjustments

• Extended-release capsules: Initial dose should be lowered; monitor closely for respiratory depression and sedation
• Extended-release tablets: Lower the initial dose to one-half the normal starting dose; monitor closely for respiratory depression and sedation

Liver Dose Adjustments

Extended-release capsules:

• Mild to moderate hepatic impairment: No dose adjustment recommended
• Severe hepatic impairment: 10 mg orally every 12 hours; monitor closely for respiratory depression and sedation

Extended-release tablets: Lower the initial dose to one-half the normal starting dose; monitor closely for respiratory depression and sedation

Dose Adjustments

Abrupt discontinuation should be avoided in the physically dependent patient:

• Extended-release capsules: Titrate the dose down every 2 to 4 days; a more gradual titration may be needed in patients showing signs and symptoms of opioid withdrawal
• Extended-release tablets: Titrate the dose down every 2 to 4 days; the titrated dose should be at least 50% of the prior dose; after reaching 20 mg once a day for 2 to 4 days, the extended-release tablets can be discontinued.

Concomitant Use with CNS depressants: Lower the recommended starting dose by 20% to 30% and consider a lower dose of the concomitant CNS depressant.

CYP450 3A4 Inducers and Inhibitors: Dose adjustments may be necessary; closely monitor patients currently taking, or discontinuing CYP450 3A4 inducers and inhibitors

Increased Risk of Respiratory Depression: Consider lower initial doses, slower titrations, or alternative analgesics.

QTc Interval Prolongation: Reduce dose by 33% to 50%; consider alternative analgesics

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for all opioids intended for outpatient use. The new FDA Opioid Analgesic REMS is a designed to assist in communicating the serious risks of opioid pain medications to patients and health care professionals. It includes a medication guide and elements to assure safe use. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

• ADDICTION, ABUSE, AND MISUSE: This drug 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 this drug and monitor all patients regularly for the development of these behaviors or conditions.
• REMS: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required 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 complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.
• LIFE-THREATENING RESPIRATORY DEPRESSION: Serious, life-threatening, or fatal respiratory depression may occur with use. Monitor for respiratory depression, especially during initiation of therapy or following a dose increase. Instruct patients to swallow capsules and tablets whole; crushing, chewing, or dissolving can cause rapid release and absorption of a potentially fatal dose of hydrocodone.
• ACCIDENTAL INGESTION of even one dose, especially by children, can result in a fatal overdose of hydrocodone.
• NEONATAL OPIOID WITHDRAWAL SYNDROME: Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
• CYP450 3A4 INTERACTION: The concomitant use of hydrocodone ER with all CYP450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used CYP450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving hydrocodone ER and any CYP450 3A4 inhibitor or inducer.
• 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 use for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required, and follow patients for signs and symptoms of respiratory depression.
• INTERACTION WITH ALCOHOL: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking hydrocodone ER. The co-ingestion of alcohol with hydrocodone ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

CONTRAINDICATIONS:

• Hypersensitivity to hydrocodone or any of the excipients
• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Known or suspected paralytic ileus and gastrointestinal obstruction

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule II

Dialysis

Data not available

Other Comments

Administration advice:
Extended-release capsules:

• Swallow whole; do not crush, dissolve, or chew the beads in the capsule
• Take orally every 12 hours

Extended-release tablets:

• Swallow whole; do not crush, dissolve, or chew
• Take orally every 24 hours
• Take 1 tablet at a time with enough water to ensure complete swallowing; do not pre-soak, lick, or otherwise wet tablets prior to placing in the mouth

General:

• This drug should be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
• Due to the risk of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, extended-release hydrocodone is for use in patients for whom alternative treatment options (non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• For patients receiving other opioid analgesics and switching to this drug or the extended-release tablet formulation, it is safer to underestimate a patient's 24-hour oral requirement and provide rescue medication than overestimate and manage an adverse reaction; there is substantial inter-patient variation in the relative potency of different opioid drugs that conversion tables are not able to capture.
• During chronic therapy, periodically reassess the continued need for opioid analgesics.
• This drug is not indicated as an as-needed (prn) analgesic

Monitoring:

• Cardiovascular: Monitor for signs of hypotension upon initiating therapy and following dose increases, especially those whose blood pressure is compromised
• Respiratory: Monitor for respiratory depression, especially within the first 24 to 72 hours.
• Gastrointestinal: Monitor for constipation and decreased bowel motility in post-operative patients.
• General: Monitor routinely for maintenance of pain control and incidence of adverse reactions.
• Psychiatric: Patients should be monitored for the development of addiction, abuse, or misuse.

Patient advice:

• Patients should be instructed to read the US FDA-approved Medication Guide each time this drug is dispensed; they should understand the safe use, serious risks, and proper storage and disposal of this drug.
• Advise patients to store this drug safely out of the sight and reach of children; accidental use by a child is a medical emergency and can result in death.
• Patients should understand that this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect their drug from theft or misuse.
• Patients should understand the risks of life-threatening respiratory depression, and be informed as to when this risk is greatest; patients should be made aware that crushing, chewing, or dissolving capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death.
• This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
• Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.
• Patients should not consume alcoholic beverages, or prescription or nonprescription products containing alcohol, while on treatment.

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