(hye droe KOE done)
Pain: Management of pain severe enough to require daily around-the-clock opioid, long-term treatment and for which alternative treatment options (eg, nonopioid analgesics or immediate release opioids) are inadequate
Limitations of use: Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve hydrocodone ER for use in patients for whom alternative treatment options (eg, nonopioid analgesics, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Hydrocodone ER is not indicated as an as-needed analgesic.
Hypersensitivity to hydrocodone or any component of the formulation; paralytic ileus (known or suspected) or gastrointestinal obstruction; significant respiratory depression; acute/severe bronchial asthma (in an unmonitored setting or without resuscitative equipment).
Hydrocodone ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patients risk prior to prescribing, and monitor all patients regularly for the development of these behaviors or conditions.
Life-threatening respiratory depression:Serious, life-threatening, or fatal respiratory depression may occur with use of hydrocodone. Monitor for respiratory depression, especially during initiation or following a dose increase. Instruct patients to swallow hydrocodone ER capsules whole; crushing, chewing, or dissolving capsules can cause rapid release and absorption of a potentially fatal dose of hydrocodone.
Accidental exposure:Accidental consumption of even 1 dose of hydrocodone ER, especially by children, can result in a fatal overdose.
Neonatal opioid withdrawal syndrome:Prolonged use of hydrocodone ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Interaction with alcohol:Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking Zohydro ER. The coingestion of alcohol with Zohydro ER may result in increased plasma levels and a potentially fatal overdose.
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 CYP3A4 inhibitor or inducer.
Pain (chronic): Oral: Note: Pain relief and adverse events should be assessed frequently. Individually titrate to a dose that provides adequate analgesia and minimizes adverse reactions. Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.
Opioid-naive patients (use as the first opioid analgesic or use in patients who are not opioid tolerant): Note: Single doses >40 mg, the 50 mg extended-release capsules (Zohydro ER), or a total daily dose ≥80 mg are only for patients who are opioid tolerant. Opioid tolerance is defined as: Patients already taking (for 1 week or more) 60 mg of oral morphine daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone daily, or an equivalent dose of another opioid.
Hysingla ER: Initial: 20 mg once daily. Dose increases may occur in increments of 10 to 20 mg every 3 to 5 days as needed to achieve adequate analgesia
Zohydro ER: Initial: 10 mg every 12 hours. Dose increases may occur in increments of 10 mg every 12 hours every 3 to 7 days as needed to achieve adequate analgesia
Conversion from other oral hydrocodone formulations to extended-release hydrocodone:
Hysingla ER: Initiate extended-release hydrocodone with the total daily dose of oral hydrocodone (mg/day) administered once daily. Dose increases may occur in increments of 10 to 20 mg every 3 to 5 days as needed to achieve adequate analgesia
Zohydro ER: Initiate extended-release hydrocodone with the total daily dose of oral hydrocodone (mg/day) divided in half for administration every 12 hours. Dose increases may occur in increments of 10 mg every 12 hours every 3 to 7 days as needed to achieve adequate analgesia
Conversion from other oral opioids (see tables): Discontinue all other around-the-clock opioids when extended-release hydrocodone is initiated. Substantial interpatient variability exists in relative potency and formulations. Therefore, it is safer to underestimate a patient 's daily oral hydrocodone requirement and provide breakthrough pain relief with rescue medication (eg, immediate release opioid) than to overestimate requirements. The following approximate oral conversion factors may be used to convert from oral opioid therapy to extended-release hydrocodone. Titrate until adequate pain relief with tolerable side effects has been achieved.
To get the approximate equivalent doses for conversion from current opioid therapy to extended-release hydrocodone, select the opioid, sum the total daily dose, then multiply by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose.
For patients on more than 1 opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals. Always round the dose down, if necessary, to the appropriate extended-release hydrocodone strength(s) available. (Note: The approximate oral conversion factors and approximate equivalent doses are only to be used for the conversion from current opioid therapy to extended-release hydrocodone).
Hysingla ER: Reduce the calculated approximate total daily dose of oral hydrocodone dose by 25%. Initiate with calculated reduced dose (mg/day) administered once daily.
Zohydro ER: Initiate with the approximate total daily dose of oral hydrocodone (mg/day) divided in half for administration every 12 hours.
Conversion Factors to Hysingla ERPrevious Oral Opioid
Approximate Oral Conversion Factor
Oxycodone
1
Methadone1
1.5
Oxymorphone
2
Hydromorphone
4
Morphine
0.5
Codeine
0.15
Tramadol
0.1
1Monitor closely; ratio between methadone and other opioid agonists may vary widely as a function of previous drug exposure. Methadone has a long half-life and may accumulate in the plasma.
Table has been converted to the following text.
Conversion Factors to Hyslinga ER
Previous oral opioid:
Oxycodone:
Approximate oral conversion factor: 1
Methadone:
Approximate oral conversion factor: 1.5
Monitor closely; ratio between methadone and other opioid agonists may vary widely as a function of previous drug exposure. Methadone has a long half-life and may accumulate in the plasma.
Oxymorphone:
Approximate oral conversion factor: 2
Hydromorphone:
Approximate oral conversion factor: 4
Morphine:
Approximate oral conversion factor: 0.5
Codeine:
Approximate oral conversion factor: 0.15
Tramadol:
Approximate oral conversion factor: 0.1
Conversion Factors to Zohydro ER1Previous Oral Opioid
Approximate Oral Conversion Factor2
1Approximate equivalent doses for conversion from current opioid therapy to Zohydro ER.
2Ratio for converting oral opioid dose to approximate Zohydro ER equivalent dose.
3Monitor closely; ratio between methadone and other opioid agonists may vary widely as a function of previous drug exposure. Methadone has a long half-life and may accumulate in the plasma.
Hydrocodone
1
Oxycodone
1
Methadone3
1
Oxymorphone
2
Hydromorphone
2.67
Morphine
0.67
Codeine
0.1
Table has been converted to the following text.
Conversion Factors to Zohydro ER (Approximate equivalent doses for conversion from current opioid therapy to Zohydro ER; Ratio for converting oral opioid dose to approximate Zohydro ER equivalent dose)
Previous oral opioid:
Hydrocodone:
Approximate oral conversion factor: 1
Oxycodone:
Approximate oral conversion factor: 1
Methadone:
Approximate oral conversion factor: 1
Monitor closely; ratio between methadone and other opioid agonists may vary widely as a function of previous drug exposure. Methadone has a long half-life and may accumulate in the plasma.
Oxymorphone:
Approximate oral conversion factor: 2
Hydromorphone:
Approximate oral conversion factor: 2.67
Morphine:
Approximate oral conversion factor: 0.67
Codeine:
Approximate oral conversion factor: 0.1
Conversion from transdermal fentanyl:
Hysingla ER: Treatment with Hysingla ER may be started 18 hours after the removal of the fentanyl transdermal patch. For every fentanyl 25 mcg per hour transdermal patch, initially substitute Hysingla ER 20 mg every 24 hours. Monitor the patient closely.
Zohydro ER: Treatment with Zohydro ER may be started 18 hours after the removal of the fentanyl transdermal patch. For every fentanyl 25 mcg per hour transdermal patch, initially substitute Zohydro ER 10 mg every 12 hours. Monitor the patient closely.
Conversion from transdermal buprenorphine:
Hysingla ER: All patients receiving transdermal buprenorphine ( ≤20 mcg/hour) should initiate therapy with Hysingla ER 20 mg every 24 hours. Monitor the patient closely.
Discontinuing therapy:
Hysingla ER: Do not abruptly discontinue Hysingla ER. When a patient no longer requires hydrocodone, gradually titrate the dose downward every 2 to 4 days to prevent signs and symptoms of withdrawal in the physically dependent patient. The next dose should be at least 50% of the prior dose. After reaching a dose of 20 mg daily for 2 to 4 days, Hysingla ER may be discontinued.
Zohydro ER: Do not abruptly discontinue Zohydro ER. When a patient no longer requires hydrocodone, gradually titrate the dose downward every 2 to 4 days to prevent signs and symptoms of withdrawal in the physically dependent patient.
Refer to adult dosing. Note: Initiate dosing at the lower end of the dosage range. Monitor closely.
Hysingla ER:
Mild impairment: No dosage adjustment necessary.
Moderate to severe impairment: Initial: Start with 50% of the initial dose; monitor closely
End-stage renal disease (ESRD): Initial: Start with 50% of the initial dose; monitor closely
Zohydro ER: Initiate therapy with a low dose; monitor closely.
Mild to moderate impairment: No dosage adjustment necessary.
Severe impairment:
Hysingla ER: Initial: Start with 50% of the initial dose; monitor closely.
Zohydro ER: Initial: 10 mg every 12 hours; monitor closely.
Administer whole; do not crush, chew, or dissolve. Crushing, chewing, or dissolving will result in uncontrolled delivery of hydrocodone and can lead to overdose or death. Do not presoak, lick or wet dosage form prior to ingestion. Capsules or tablets should be administered one at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.
Store at 25 ‚ °C (77 ‚ ° F); excursions are permitted between 15 ‚ °C and 30 ‚ °C (59 ‚ °F and 86 ‚ °F).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule ER 12 Hour Abuse-Deterrent, Oral, as bitartrate:
Zohydro ER: 10 mg (60 ea); 15 mg (60 ea); 20 mg (60 ea); 30 mg (60 ea); 40 mg (60 ea); 50 mg (60 ea) [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
Capsule Extended Release 12 Hour, Oral, as bitartrate:
Zohydro ER: 10 mg [DSC], 15 mg [DSC], 20 mg [DSC], 30 mg [DSC], 40 mg [DSC], 50 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
Tablet ER 24 Hour Abuse-Deterrent, Oral, as bitartrate:
Hysingla ER: 20 mg [contains fd&c blue #2 aluminum lake]
Hysingla ER: 30 mg, 40 mg, 60 mg, 80 mg
Hysingla ER: 100 mg [contains fd&c blue #2 aluminum lake]
Hysingla ER: 120 mg
Alcohol (Ethyl): May enhance the CNS depressant effect of HYDROcodone. Alcohol (Ethyl) may increase the serum concentration of HYDROcodone. Management: Patients using the Zohydro ER brand of extended-release hydrocodone must not consume alcohol or alcohol-containing products due to possibly fatal outcomes. Other hydrocodone products are also expected to interact, but to a less significant degree. Avoid combination
Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification
Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy
Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification
Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Ceritinib: May increase the serum concentration of CYP3A4 Substrates. Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination
CYP2D6 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of HYDROcodone. Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of HYDROcodone. Monitor therapy
CYP3A4 Inducers (Weak): May decrease the serum concentration of HYDROcodone. Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of HYDROcodone. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of HYDROcodone. Monitor therapy
CYP3A4 Inhibitors (Weak): May increase the serum concentration of HYDROcodone. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy
Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy
Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification
Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
MAO Inhibitors: May enhance the adverse/toxic effect of HYDROcodone. Management: Consider alternatives to this combination when possible. Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy
MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification
Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Nalmefene: May diminish the therapeutic effect of Analgesics (Opioid). Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification
Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification
Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of HYDROcodone. Management: Reduce the hydrocodone dose by 50% during concurrent use of ombitasvir, paritaprevir, and ritonavir; monitor closely for both analgesic effectiveness and for signs of toxicity or withdrawal. Consider therapy modification
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of HYDROcodone. Management: Reduce the hydrocodone dose by 50% during concurrent use of ombitasvir, paritaprevir, ritonavir, and dasabuvir; monitor closely for both analgesic effectiveness and for signs of toxicity or withdrawal. Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination
Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification
Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination
Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification
Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy
QuiNIDine: May decrease serum concentrations of the active metabolite(s) of HYDROcodone. Monitor therapy
Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy
Serotonin Modulators: Analgesics (Opioid) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification
St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification
Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification
Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification
Pain relief, respiratory and mental status, blood pressure; signs of misuse, abuse, and addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan, 2013)
Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).
1% to 10%:
Cardiovascular: Hypertension ( ≥1% to <5%), peripheral edema (3%)
Central nervous system: Chills ( ≥1% to <5%), sedation ( ≥1% to <5%), insomnia (3%), dizziness (2% to 3%), drowsiness (1%), anxiety, depression, falling, lethargy, migraine, pain, paresthesia
Dermatologic: Hyperhidrosis, night sweats, pruritus, skin rash
Endocrine & metabolic: Dehydration, hot flash, hypokalemia, increased gamma-glutamyl transferase, increased serum cholesterol
Gastrointestinal: Nausea (7% to 8%), constipation (3% to 8%), vomiting (5% to 6%), diarrhea ( ≥1% to <5%), dyspepsia ( ≥1% to <5%), gastroenteritis ( ≥1% to <5%), upper abdominal pain ( ≥1% to <5%), viral gastroenteritis ( ≥1% to <5%), abdominal pain (3%), decreased appetite (2%), abdominal distress, gastroesophageal reflux disease, xerostomia
Genitourinary: Urinary tract infection (5%)
Hematologic & oncologic: Bruise
Infection: Influenza (3%)
Neuromuscular & skeletal: Back pain (4%), muscle spasm (3%), tremor (3%), arthralgia, bone fracture (foot), injury to the joint, joint sprain, limb pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, osteoarthritis, strain
Otic: Tinnitus (2%)
Respiratory: Bronchitis ( ≥1% to <5%), nasal congestion ( ≥1% to <5%), nasopharyngitis ( ≥1% to <5%), oropharyngeal pain ( ≥1% to <5%), sinusitis ( ≥1% to <5%), upper respiratory tract infection (3%), cough, dyspnea
Miscellaneous: Fever, laceration
<1% (Limited to important or life-threatening): Abdominal distention, abnormality in thinking, altered mental status, choking sensation, confusion, decreased libido, drug-induced hypersensitivity, drug withdrawal, dysphagia, edema, esophageal obstruction, flushing, hypogonadism (Brennan 2013; Debono, 2011), hypotension, hypoxia, increased thirst, irritability, malaise, mood changes, muscle twitching, opioid dependence, orthostatic hypotension, palpitations, presyncope, prolonged Q-T interval on ECG, respiratory depression, retching, syncope, urinary retention, weakness
Hysingla ER: Cmax values 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, respectively.
Zohydro ER: Cmax values were 15%, 48%, and 41% higher and AUC values were 15%, 57%, and 44% higher in patients with mild, moderate, and severe renal impairment, respectively.
Hysingla ER: Cmax values were -6%, 5%, and 5% and AUC values were -14%, 13%, and 4% in patients with mild, moderate, or severe hepatic impairment, respectively.
Zohydro ER: Cmax values were 8% to 10% higher in patients with hepatic impairment while AUC values were 10% and 26% higher in patients with mild and moderate hepatic impairment, respectively.
Concerns related to adverse effects:
- Cardiovascular effects: QTc prolongation has been observed with hydrocodone ER tablet doses >160 mg daily. Use with caution in patients with heart failure, bradyarrhythmias, electrolyte abnormalities or using other drugs known to prolong the QTc interval. Avoid use in patients with congenital long QT syndrome. If patients develop QTc prolongation, consider dose reduction of 33% to 50% or change to an alternate analgesic.
- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery, driving).
- Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration.
- Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (codeine, hydromorphone, levorphanol, oxycodone, oxymorphone).
- Respiratory depression: [U.S. Boxed Warning]: May cause serious, life-threatening, or fatal respiratory depression. Monitor closely for respiratory depression, especially during initiation or dose escalation. Patients should swallow capsules or tablets whole; crushing, chewing, or dissolving can cause rapid release and a potentially fatal dose. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Disease related concerns:
- Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions, including biliary tract disease (eg, acute pancreatitis). May cause spasm of the sphincter of Oddi. May worsen gastrointestinal ileus due to reduced GI motility. Contraindicated in patients with paralytic ileus.
- Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addisons disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan, 2013).
- Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; may cause constriction of sphincter of Oddi.
- CNS depression/coma: Avoid use in patients with CNS depression or coma as these patients are susceptible to intracranial effects of CO2 retention.
- Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur. Opioid effects on pupillary response and consciousness may obscure other signs of increased ICP.
- Hepatic impairment: Use with caution in patients with hepatic dysfunction; dose adjustment may be warranted.
- Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).
- Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
- Renal impairment: Use with caution in patients with renal dysfunction; dose adjustment may be warranted.
- Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating with hydrocodone; even therapeutic doses may decrease respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients.
- Seizures: Use with caution in patients with a history of seizure disorders.
- Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).
- Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
- CYP 3A4 interactions: [US Boxed Warning]: Use with all CYP3A4 inhibitors may result in increased effects and potentially fatal respiratory depression. In addition, discontinuation of a concomitant CYP3A4 inducer may result in increased hydrocodone concentrations. Monitor patients receiving any CYP3A4 inhibitor or inducer.
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Sedatives: Effects may be potentiated when used with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).
Special populations:
- Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.
- Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Decrease initial dose.
- Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
Dosage form specific issues:
- Dysphagia/choking: Hysingla ER: Esophageal obstruction, dysphagia, and choking have occurred. Patients with underlying gastrointestinal (GI) disorders (eg, esophageal or colon cancer) with a small GI lumen are at greater risk. Consider the use of alternative analgesics in these patients. Do not presoak, lick, or wet tablets prior to ingestion; take 1 tablet at a time with enough water to ensure complete swallowing immediately after placing in mouth.
- Ethanol use: Zohydro ER: [US Boxed Warning]: Do not administer Zohydro ER with alcoholic beverages or ethanol-containing products because of the risk of increased plasma levels and potentially fatal overdose of hydrocodone. Alcohol may disrupt extended-release characteristic of product.
Other warnings/precautions:
- Abuse/misuse/diversion: [US Boxed Warning]: Users are exposed to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient 's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Risk of opioid abuse is increased in patients with a history or family history of alcohol or drug abuse or mental illness. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages ( ≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).
- Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).
- Accidental exposure: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of hydrocodone.
- Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Taper dose gradually when discontinuing.
C
Adverse events were observed in some animal reproduction studies. Opioid analgesics cross the placenta. In humans, birth defects, including some heart defects, have been associated with maternal use of opioid analgesics, including hydrocodone, during the first trimester of pregnancy (Broussard, 2011).
[U.S. Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur; monitoring of the neonate is recommended. The minimum effective dose should be used if opioids are needed (Chou, 2009). Neonatal abstinence syndrome following opioid exposure may present with autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high pitched crying, increased muscle tone, irritability, seizure, tremor) symptoms (Dow, 2012; Hudak, 2012).
Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan, 2013).
Long-acting products, such as Zohydro ER, are not recommended for analgesia during and immediately prior to labor and delivery; if needed, shorter-acting analgesics are more appropriate.
Hydrocodone, as with other opioid analgesics, binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.
Hepatic: O-demethylation via primarily CYP2D6 to hydromorphone (major, active metabolite with ~10- to 33-fold higher or as much as a >100-fold higher binding affinity for the mu-opioid receptor than hydrocodone); N-demethylation via CYP3A4 to norhydrocodone (major metabolite); and ~40% of metabolism/clearance occurs via other non-CYP pathways, including 6-ketosteroid reduction to 6-alpha-hydrocol and 6-beta-hydrocol, and other elimination pathways (eg, fecal, biliary, intestinal, renal) (Hutchinson, 2004; Volpe, 2011; Zhou, 2009)
Urine (26% of single dose in 72 hours, with ~12% as unchanged drug, 5% as norhydrocodone, 4% as conjugated hydrocodone, 3% as 6-hydrocodol, and 0.21% as conjugated 6-hydromorphol [Zhou, 2009])
Plasma: Hysingla ER: 6 to 30 hours; Zohydro ER: ~5 hours
Hysingla ER: ~7 to 9 hours; Zohydro ER: ~8 hours (plasma)
36%
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience fatigue, vomiting, or nausea. Have patient report immediately to prescriber slow breathing, shallow breathing, trouble breathing, signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), severe dizziness, passing out, angina, swelling of arms or legs, burning or numbness feeling, tachycardia, illogical thinking, severe constipation, severe abdominal pain, loss of strength and energy, mood changes, memory impairment, severe headache, seizures, dysphagia, or pain with urination (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.