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Hydrocodone

Medically reviewed by Drugs.com. Last updated on Aug 1, 2020.

Pronunciation

(hye droe KOE done)

Index Terms

  • Hydrocodone Bitartrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Extended Release 12 Hour, Oral, as bitartrate:

Zohydro ER: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Generic: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg

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

Brand Names: U.S.

  • Hysingla ER
  • Zohydro ER

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

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.

Distribution

~1,300 to 1,400 L

Metabolism

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)

Excretion

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])

Time to Peak

Plasma: Hysingla ER: 6 to 30 hours; Zohydro ER: ~5 hours

Half-Life Elimination

Hysingla ER: ~7 to 9 hours; Zohydro ER: ~8 hours (plasma)

Protein Binding

36%

Special Populations: Renal Function Impairment

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.

Special Populations: Hepatic Function Impairment

Hysingla ER: Cmax values were -6%, 5%, and 5% higher and AUC values were -14%, 13%, and 4% higher 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.

Use: Labeled Indications

Cough (pdp-Hydrocodone [Canadian product]): Control of exhausting, nonproductive cough.

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

Limitations of use: 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.

Contraindications

Hypersensitivity (eg, anaphylaxis) to hydrocodone or any component of the formulation; GI obstruction, including paralytic ileus (known or suspected); significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment.

Canadian labeling: Additional contraindications (not in US labeling): Suspected surgical abdomen (eg, acute appendicitis or pancreatitis); chronic obstructive airway; acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury; concurrent use with or within 14 days of monoamine oxidase inhibitor therapy; pediatric patients <6 years of age.

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Cough (pdp-Hydrocodone [Canadian product]): Usual dose: 5 mL every 4 hours. Maximum single dose: 15 mL/dose. Maximum total daily dose: 30 mL in 24 hours.

Pain management: 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 or patients who are not opioid tolerant: Note: Single doses >40 mg (Zohydro ER) or a total daily dose ≥80 mg (Hysingla ER) or >80 mg (Zohydro ER) are only for patients who are opioid tolerant. Opioid tolerance is defined as: Patients already taking (for ≥1 week) at least 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, 60 mg oral hydrocodone 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:

Hysingla ER: Initiate hydrocodone ER 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 hydrocodone ER 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 hydrocodone ER 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 hydrocodone ER.

To get the approximate equivalent doses for conversion from current opioid therapy to hydrocodone ER, select the opioid, sum the total daily dose, then multiply by the approximate oral conversion factor to calculate the approximate oral hydrocodone ER daily dose. Initiate with the total daily dose of oral hydrocodone ER (mg/day) once daily (Hysingla ER) or divided in half for administration every 12 hours (Zohydro ER). Titrate until adequate pain relief with tolerable side effects has been achieved.

For patients on >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 hydrocodone ER strength(s) available. Reduce the calculated total daily dose of oral hydrocodone ER dose by 25%. Initiate with the total daily dose of oral hydrocodone ER (mg/day) once daily (Hysingla ER) or divided in half for administration every 12 hours (Zohydro ER). Titrate until adequate pain relief with tolerable side effects has been achieved.

Conversion Factors to Hysingla ER

Previous 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.

Conversion Factors to Zohydro ER1

Previous 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

Conversion from transdermal fentanyl: Treatment 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 or Zohydro ER 10 mg every 12 hours. Monitor patient closely.

Conversion from transdermal buprenorphine:Hysingla ER: Initial: 20 mg every 24 hours in patients receiving ≤ 20 mcg/hour buprenorphine transdermal. Monitor patient closely.

Discontinuation of therapy: When discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal universal tapering schedule for all patients has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Tapering schedules should be individualized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered. An even slower taper may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2018).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing. Initiate dosing at the lower end of the dosage range. Monitor closely.

Administration

Oral:

Capsule/tablet: 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.

Solution: pdp-Hydrocodone 1 mg/mL [Canadian product]: Administer after meals and at bedtime with food or milk.

Bariatric surgery: Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Do not cut, crush, or chew. No IR form available as single ingredient. Consider switching to an IR hydrocodone/acetaminophen product if patient can tolerate acetaminophen or an equivalent dose of a different single-ingredient opioid.

Storage

Store at 25°C (77° F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Alvimopan: Opioid Agonists 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 Opioid Agonists. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. 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 (High risk with Inhibitors). 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. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2D6 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Exceptions: FLUoxetine; PARoxetine. 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 Inhibitors (Moderate): May increase the serum concentration of HYDROcodone. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of HYDROcodone. Exceptions: Nefazodone. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists 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 (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of HYDROcodone. Management: Consider alternatives to this combination when possible. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Nefazodone: Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for increased opioid effects, including fatal respiratory depression, when these agents are combined and consider opioid dose reductions until stable drug effects are achieved. Additionally, monitor for serotonin syndrome/serotonin toxicity. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. 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

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interupt oxybate salt treatment during short-term opioid use. Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Opioid Agonists 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

PHENobarbital: May enhance the CNS depressant effect of HYDROcodone. PHENobarbital may decrease the serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Primidone: May enhance the CNS depressant effect of HYDROcodone. Primidone may decrease the serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Consider therapy modification

Ramosetron: Opioid Agonists 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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for decreased therapeutic response (eg, analgesia) and opioid withdrawal when coadministered with SSRIs that strongly inhibit CYP2D6. Additionally, monitor for serotonin syndrome/serotonin toxicity if these drugs are combined. Monitor therapy

Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: FLUoxetine; Isocarboxazid; Linezolid; Methylene Blue; Nefazodone; PARoxetine; Phenelzine; Tranylcypromine. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 Opioid Agonists. 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

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: 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 (High risk with Inducers). 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

Test Interactions

Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered.

Adverse Reactions

>10%: Gastrointestinal: Constipation (3% to 14%), nausea (7% to 12%)

1% to 10%:

Cardiovascular: Hypertension (≥1% to <5%), peripheral edema (3%)

Central nervous system: Headache (6%), chills (≥1% to <5%), sedation (≥1% to <5%), anxiety (4%), insomnia (3%), dizziness (2% to 3%), drowsiness (1% to 3%), fatigue (2%), depression, falling, lethargy, migraine, pain, paresthesia

Dermatologic: Pruritus (1%), hyperhidrosis, night sweats, skin rash

Endocrine & metabolic: Dehydration, hot flash, hypokalemia, increased gamma-glutamyl transferase, increased serum cholesterol

Gastrointestinal: Vomiting (5% to 6%), dyspepsia (≥1% to <5%), gastroenteritis (≥1% to <5%), upper abdominal pain (≥1% to <5%), viral gastroenteritis (≥1% to <5%), diarrhea (4%), abdominal pain (3%), decreased appetite (2%), xerostomia (1%), abdominal distress, gastroesophageal reflux disease

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%, postmarketing and/or case reports: Abdominal distention, abnormality in thinking, agitation, altered mental status, anaphylaxis, choking sensation, confusion, decreased libido, drug-induced hypersensitivity, drug withdrawal, dysphagia, edema, erythema, esophageal obstruction, flushing, hypogonadism (Brennan 2013; Debono, 2011), hypotension, hypoxia, increased thirst, intestinal obstruction, irritability, malaise, mood changes, muscle twitching, opioid dependence, orthostatic hypotension, palpitations, pancreatitis, presyncope, prolonged QT interval on ECG, respiratory depression, retching, syncope, urinary retention, weakness

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

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 patient's risk prior to prescribing hydrocodone ER and monitor all patients regularly for the development of these behaviors and conditions.

Opioid analgesic risk evaluation and mitigation strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a 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 health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program and 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 of hydrocodone ER. Monitor for respiratory depression, especially during initiation of hydrocodone or following a dose increase. Instruct patients to swallow hydrocodone ER whole; crushing, chewing, or dissolving hydrocodone can cause rapid release and absorption of a potentially fatal dose of hydrocodone.

Accidental ingestion:

Accidental ingestion of even 1 dose of hydrocodone ER, especially by children, can result in a fatal overdose of hydrocodone.

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.

Cytochrome P450 3A4 Interaction:

The concomitant use of hydrocodone ER with all cytochrome P450 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 cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving hydrocodone and any CYP3A4 inhibitor or inducer.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of hydrocodone ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Interaction with alcohol (Zohydro ER):

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 may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: QTc prolongation has been observed with hydrocodone ER following doses of 160 mg/day. 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).

• Constipation: May cause constipation which may be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• 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. Avoid use in patients with circulatory shock.

• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (codeine, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Swallow ER 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.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be needed.

• 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]).

• Obesity: Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with moderate to severe renal impairment; dose adjustment may be needed.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of hydrocodone ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

• CYP 3A4 interactions: [US Boxed Warning]: Use with all CYP3A4 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 concomitant CYP 3A4 inducer may result in increased hydrocodone concentrations. Monitor patients receiving hydrocodone ER and any CYP3A4 inhibitor or inducer.

• Ethanol use: Zohydro ER: [US Boxed Warning]: Do not administer hydrocodone 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.

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. Consider the use of alternative nonopioid analgesics in these patients.

• 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. Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated 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. 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 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.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances; provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.

• Abuse/misuse/diversion: [US Boxed Warning]: Use exposes patients and other users 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. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. 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]).

• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of hydrocodone.

• 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, nonsteroidal anti-inflammatory drugs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid 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]).

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• REMS program: [US Boxed Warning]: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required. Drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are 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.

• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; bowel function; signs/symptoms 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]).

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan 2013).

Pregnancy Considerations

Opioids cross the placenta.

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]).

[US Boxed Warning]: Prolonged use of hydrocodone 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. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.

Hydrocodone is not commonly used to treat pain during labor and immediately postpartum (ACOG 209 2019) or chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009).

Patient Education

What is this drug used for?

• It is used to ease pain.

• It is only to be used when around-the-clock (continuous) care is needed for a long time. It is also only to be used when other pain drugs do not treat your pain well enough or you cannot take them.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Common cold symptoms

• Throwing up

• Upset stomach

• Headache

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Slow breathing

• Shallow breathing

• Trouble breathing

• Severe fatigue

• Severe dizziness

• Passing out

• Chest pain

• Swelling of arms or legs

• Fast heartbeat

• Confusion

• Severe constipation

• Severe stomach pain

• Mood changes

• Trouble with memory

• Seizures

• Noisy breathing

• Breathing problems during sleep (sleep apnea)

• Sexual dysfunction (men)

• No menstrual periods

• Loss of sex drive

• Trouble getting pregnant

• Trouble swallowing

• Choking

• Urinary tract infection like blood in your urine, burning or painful urination, passing a lot of urine, fever, lower stomach pain, or pelvic pain

• Adrenal gland problems like severe upset stomach, throwing up, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, not hungry, or weight loss

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe upset stomach, or severe diarrhea

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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