HYDROcodone (Lexi-Drugs)

ALERT: US Boxed Warning
  Addiction, abuse, and misuse:
  Opioid analgesic risk evaluation and mitigation strategy (REMS)
  Life-threatening respiratory depression:
  Accidental ingestion:
  Neonatal opioid withdrawal syndrome:
  Cytochrome P450 3A4 Interaction:
  Risks from concomitant use with benzodiazepines or other CNS depressants:
  Interaction with alcohol (Zohydro ER):
Special Alerts
  Opioid-Containing Cough and Cold Products Safety AlertFebruary 2019
Pronunciation

(hye droe KOE done)

Brand Names: US

Hysingla ER; Zohydro ER

Pharmacologic Category

Analgesic, Opioid

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 tolerantNote: Single doses >40 mg (Zohydro ER) or >60 mg (Vantrela ER), a total daily dose ≥80 mg (Hysingla ER), >80 mg (Zohydro ER) or >120 mg (Vantrela ER), and Vantrela ER 90 mg tablets are only for patients who are opioid tolerant. Opioid tolerance is defined as: Patients already taking (for 1 week or more) 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

Vantrela ER: Initial: 15 mg every 12 hours. Dose increases may occur every 3 to 7 days as needed to achieve adequate analgesia (maximum: 180 mg/day).

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

Vantrela 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 every 3 to 7 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 (Vantrela ER, Zohydro ER). Titrate until adequate pain relief with tolerable side effects has been achieved.

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 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 (Vantrela ER, 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 Vantrela ER1
Previous Oral Opioid Approximate Oral Conversion Factor2
1Approximate equivalent doses for conversion from current opioid therapy to Vantrela ER.
2Ratio for converting oral opioid dose to approximate Vantrela 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.
4Initiate regimen as opioid-naive patients or patients who are not opioid tolerant.
Hydromorphone 2
Methadone3 1.5
Oxymorphone 1.5
Oxycodone 0.75
Hydrocodone 0.5
Morphine 0.5
Codeine 0.075
Meperidine 0.05
Tramadol4 None
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 Vantrela ER 15 mg every 12 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).

Dosing: Geriatric

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

Dosing: Renal Impairment: Adult

US labeling:

Hysingla ER, Vantrela ER:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: Initial: Start with 50% of the initial dose; titrate carefully; monitor closely.

End-stage renal disease (ESRD): Initial: Start with 50% of the initial dose; titrate carefully; monitor closely.

Zohydro ER: There are no specific dosage adjustments provided in the manufacturer’s labeling; initiate therapy with a low dose and monitor closely.

Canadian labeling:

pdp-Hydrocodone: There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution.

Dosing: Hepatic Impairment: Adult

US labeling:

Mild to moderate impairment:

Hysingla ER, Zohydro ER: No dosage adjustment necessary.

Vantrela ER: Initial: Start with 50% of the initial dose; titrate carefully; monitor closely.

Severe impairment:

Hysingla ER: Initial: Start with 50% of the initial dose; monitor closely.

Vantrela ER: Use is not recommended.

Zohydro ER: Initial: 10 mg every 12 hours; monitor closely.

Canadian labeling:

pdp-Hydrocodone: There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution.

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.

Clinical Practice Guidelines

Patient Safety:

“CDC Guideline for Prescribing Opioids for Chronic Pain,” 2016

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.

Storage/Stability

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

Medication Patient Education with HCAHPS Considerations

• 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 common cold symptoms, vomiting, or nausea. Have patient report immediately to prescriber slow breathing, shallow breathing, difficulty breathing, signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), severe fatigue, severe dizziness, passing out, angina, swelling of arms or legs, burning or numbness feeling, tachycardia, confusion, severe constipation, severe abdominal pain, severe loss of strength and energy, mood changes, memory impairment, severe headache, seizures, sexual dysfunction (men), amenorrhea, loss of libido, infertility, difficulty swallowing, painful urination, choking, signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea) (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.

Medication Safety Issues
  Sound-alike/look-alike issues:
  High alert medication:
REMS Components

Opioids for analgesic use: Elements to Assure Safe Use; Medication Guide

REMS Programs
Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Hysingla ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206627s007s008lbl.pdf#page=36

Vantrela ER: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207975s000lbl.pdf#page=39

Zohydro ER: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/202880s009s010lbl.pdf#page=28

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 MAOI therapy

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.

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 sexual dysfunction, infertility, 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. Vantrela ER is not recommended in patients with severe hepatic impairment.

• 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-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:

• 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.

• 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.

• 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:

• 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. NSAIDs, 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.

• 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.

Pregnancy Considerations

[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.

Opioids cross the placenta. Maternal use of opioids may be associated with birth defects, poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). 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.

Agents other than hydrocodone are recommended to treat maternal pain during labor and immediately postpartum (ACOG 177 2017) as well as chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009; Kahan 2011).

Breast-Feeding Considerations

Hydrocodone and the active metabolite hydromorphone are present in breast milk.

The relative infant dose (RID) of hydrocodone (immediate release product) was calculated in one study to be 0.2% to 9% when compared to a weight-adjusted maternal dose of 44 to 423.2 mcg/kg/day.

In general, breastfeeding is considered acceptable when the RID is <10 (Anderson 2016; Ito 2000). Cumulative exposure from hydrocodone and hydromorphone should be considered.

The RID of hydrocodone was calculated using milk concentrations of 1.6 to 99.6 mcg/mL, providing an estimated daily infant dose via breast milk of 0.2 to 14.9 mcg/kg/day. These milk concentrations were obtained following maternal administration of oral hydrocodone in combination with acetaminophen. Hydromorphone was also detected in breast milk (range: 0.2 to 86.7 mcg/L), providing a neonatal dose of 2.1 mcg/kg/day (range: 0.03 to 13 mcg/kg/day) (Sauberan 2011).

Grogginess and sleepiness were reported in a mother and breastfeeding infant following maternal use of hydrocodone 10 mg in combination with acetaminophen 650 mg (two tablets every 4 hours) (Bodley 1997). Withdrawal symptoms may occur when maternal use is discontinued or breastfeeding is stopped.

Current guidelines note that nonopioid analgesics are preferred for postpartum pain in breastfeeding women (Montgomery 2012). If hydrocodone is needed, high doses (≥10 mg), doses >40 mg/day, or frequent administration should be avoided (Montgomery 2012; Sauberan 2011).

Note: Information related to hydrocodone and breastfeeding is from studies using short acting products, not the extended release formulation. In addition, maternal CYP2D6 status was not evaluated (Anderson 2007; Sauberan 2011).

When opioids are needed in breastfeeding women, the lowest effective dose for the shortest duration of time should be used to limit adverse events in the mother and breastfeeding infant. In general, a single occasional dose of an opioid analgesic may be compatible with breastfeeding (WHO 2002). Breastfeeding women using opioids for postpartum pain or for the treatment of chronic maternal pain should monitor their infants for drowsiness, sedation, feeding difficulties, or limpness (ACOG 177 2017; Montgomery 2012; Sachs 2013). Withdrawal symptoms may occur when maternal use is discontinued or breastfeeding is stopped. Due to the potential for serious adverse reactions, breastfeeding is not recommended by the manufacturer.

Lexicomp Pregnancy & Lactation, In-Depth
Briggs’ Drugs in Pregnancy & Lactation
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 Q-T interval on ECG, respiratory depression, retching, syncope, urinary retention, weakness

Metabolism/Transport Effects

Substrate of CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions 

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. Risk X: Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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.Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: 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. Risk C: Monitor therapy

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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Risk D: Consider therapy modification

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

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

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

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

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

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification

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

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

CNS Depressants: May enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. Risk D: Consider therapy modification

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

CYP2D6 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of HYDROcodone. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of HYDROcodone. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of HYDROcodone. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of HYDROcodone. Risk C: 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). Risk D: Consider therapy modification

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

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

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

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification

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

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: 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. Risk D: Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Risk D: Consider therapy modification

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

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. Risk D: Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: 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. Risk D: Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification

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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: 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. Risk D: 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. Risk D: 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.Risk X: Avoid combination

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

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

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. Risk D: Consider therapy modification

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

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

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: 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. Risk D: Consider therapy modification

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Risk D: Consider therapy modification

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

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

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

Serotonin Modulators: Opioid Agonists may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Risk C: Monitor therapy

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

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: 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. Risk D: Consider therapy modification

St John’s Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: 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. Risk D: Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: 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. Risk D: Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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. Risk D: Consider therapy modification

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

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: 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. Risk D: Consider therapy modification

Food Interactions

Ethanol may disrupt extended-release characteristics and increase plasma levels of hydrocodone potentially leading to fatal overdose. Management: Do not administer hydrocodone ER with alcoholic beverages or ethanol-containing products.

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.

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]).

Product Availability

Vantrela ER (hydrocodone bitartrate extended-release tablets): FDA approved January 2017; anticipated availability is currently unknown.

Controlled Substance

C-II

Dosage Forms: US

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

Anatomic Therapeutic Chemical (ATC) Classification
  • R05DA03
Generic Available (US)

No

Pricing: US

Capsule ER 12 Hour Abuse-Deterrent (Zohydro ER Oral)

10 mg (per each): $11.11

15 mg (per each): $11.87

20 mg (per each): $12.25

30 mg (per each): $12.63

40 mg (per each): $13.01

50 mg (per each): $13.57

Tablet ER 24 Hour Abuse-Deterrent (Hysingla ER Oral)

20 mg (per each): $11.33

30 mg (per each): $16.54

40 mg (per each): $22.29

60 mg (per each): $30.86

80 mg (per each): $41.61

100 mg (per each): $52.95

120 mg (per each): $58.67

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer’s AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Distribution: ~1,300 to 1,400 L

Protein binding: 36%

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)

Half-life elimination: Hysingla ER: ~7 to 9 hours; Vantrela ER: ~11 to 12 hours; Zohydro ER: ~ 8 hours (plasma)

Time to peak, plasma: Hysingla ER: 6 to 30 hours; Vantrela ER: ~8 hours; Zohydro ER: ~5 hours

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)

Pharmacodynamics/Kinetics: Additional Considerations

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.

Vantrela ER: Cmax values were ~ 25% and 50% higher and AUC values were up to ~70% higher in patients with moderate or severe renal impairment, 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.

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.

Vantrela ER: Cmax values were ~30% higher and AUC values were ~70% higher in patients with moderate impairment.

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.

Index Terms

Hydrocodone Bitartrate; Vantrela ER

FDA Approval Date
October 25, 2013
References

Abele W. Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther. 2002;27(6)391-401.[PubMed 12472978]

ACOG Committee on Practice Bulletins—Obstetrics. Practice bulletin no. 177: obstetric analgesia and anesthesia. Obstet Gynecol. 2017;129(4):e73-e89.[PubMed 28333819]

Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52.[PubMed 27060684]

Anderson PO, Sauberan JB, Lane JR, Rossi SS. Hydrocodone excretion into breast milk: the first two reported cases. Breastfeed Med. 2007;2(1):10-14.[PubMed 17661614]

Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc. 2015;90(6):828-842. doi: 10.1016/j.mayocp.2015.04.003.[PubMed 26046416]

Bodley V, Powers D. Long-term treatment of a breastfeeding mother with fluconazole-resolved nipple pain caused by yeast: a case study. J Hum Lact. 1997;13(4):307-311.[PubMed 9429366]

Brennan MJ. The effect of opioid therapy on endocrine function. Am J Med. 2013;126(3)(suppl 1):S12-S18. doi: 10.1016/j.amjmed.2012.12.001.[PubMed 23414717]

Broussard CS, Rasmussen SA, Reefhuis J, et al; National Birth Defects Prevention Study. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol. 2011;204(4):314.[PubMed 21345403]

Centers for Disease Control and Prevention (CDC). Common elements in guidelines for prescribing opioids for chronic pain. https://www.cdc.gov/drugoverdose/pdf/common_elements_in_guidelines_for_prescribing_opioids-a.pdf. Published 2015. Accessed September 13, 2018.

Chou R, Fanciullo GJ, Fine PG, et al; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.[PubMed 19187889]

Debono M, Chan S, Rolfe C, Jones TH. Tramadol-induced adrenal insufficiency. Eur J Clin Pharmacol. 2011;67(8):865-867.[PubMed 21243342]

Dow K, Ordean A, Murphy-Oikonen J, et al; Neonatal Abstinence Syndrome Work Group. Neonatal abstinence syndrome clinical practice guidelines for Ontario. J Popul Ther Clin Pharmacol. 2012;19(3):e488-e506.[PubMed 23241498]

Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016 [published correction appears in MMWR Recomm Rep. 2016;65(11):295]. MMWR Recomm Rep. 2016;65(1):1-49. doi: 10.15585/mmwr.rr6501e1.[PubMed 26987082]

Hudak ML, Tan RC; Committee On Drugs, Committee on Fetus and Newborn, American Academy of pediatrics. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540-e560.[PubMed 22291123]

Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol. 2004;57(3):287-297.[PubMed 14998425]

Hysingla ER (hydrocodone bitartrate) [prescribing information]. Stamford, CT: Purdue Pharma L.P.; September 2018.

Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126.[PubMed 10891521]

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Montgomery A, Hale TW, Academy Of Breastfeeding Medicine. ABM clinical protocol #15: analgesia and anesthesia for the breastfeeding mother, revised 2012. Breastfeed Med. 2012;7(6):547-553.[PubMed 23215911]

pdp-Hydrocodone (hydrocodone bitartrate syrup) [product monograph]. Montreal, Quebec, Canada: Pendopharm; June 2018.

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Sauberan JB, Anderson PO, Lane JR, et al. Breast milk hydrocodone and hydromorphone levels in mothers using hydrocodone for postpartum pain. Obstet Gynecol. 2011;117(3):611-617.[PubMed 21343764]

Sevarino K. Medically supervised opioid withdrawal during treatment for addiction. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 13, 2018.

Vantrela ER (hydrocodone) [prescribing information]. North Wales, PA: Teva; January 2017.[PubMed 21343764]

Volpe DA, McMahon Tobin GA, Mellon RD, et al. Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol. 2011;59(3):385-390.[PubMed 21215785]

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Zohydro ER (hydrocodone) [prescribing information]. Morristown, NJ: Pernix Therapeutics; September 2018.

Brand Names: International

Dicodid (SE); Hydrocodon (CH); Hydrokon Naf (NO); Tucodil (SE); Tucodil Mite (SE)

Hydrocodone (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(hye droe KOE done)

Brand Names: US

Hysingla ER; Zohydro ER

Brand Names: Canada

pdp-Hydrocodone

Warning
  • This drug may be habit-forming with long-term use.
  • This drug is a strong pain drug that can put you at risk for addiction, abuse, and misuse. Misuse or abuse of this drug can lead to overdose and death. Talk with your doctor.
  • You will be watched closely to make sure you do not misuse, abuse, or become addicted to this drug.
  • Swallow whole. Do not chew, break, crush, or dissolve before swallowing. Doing these things can cause very bad side effects and death.
  • Even one dose of this drug may be deadly if it is taken by someone else or by accident, especially in children. If this drug is taken by someone else or by accident, get medical help right away.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • This drug may cause very bad and sometimes deadly breathing problems. Call your doctor right away if you have slow, shallow, or trouble breathing.
  • The chance of very bad and sometimes deadly breathing problems may be greater when you first start this drug or anytime your dose is raised.
  • Do not take with alcohol or products that have alcohol. Unsafe and sometimes deadly effects may happen.
  • Using this drug for a long time during pregnancy may lead to withdrawal in the newborn baby. This can be life-threatening. Talk with the doctor.
  • This drug has an opioid drug in it. The use of opioid drugs along with a benzodiazepine drug or other drugs that may make you drowsy or slow your actions has led to very bad side effects. Side effects that have happened include slowed or trouble breathing and deaths. Benzodiazepine drugs include drugs like alprazolam, diazepam, and lorazepam. Benzodiazepine drugs are used to treat many health problems like anxiety, trouble sleeping, or seizures. Talk with the doctor.
  • Many drugs interact with this drug and can raise the chance of side effects like deadly breathing problems. Talk with your doctor and pharmacist to make sure it is safe to use this drug with all of your drugs.
  • Get medical help right away if you feel very sleepy, very dizzy, or if you pass out. Caregivers or others need to get medical help right away if the patient does not respond, does not answer or react like normal, or will not wake up.
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.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to hydrocodone or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Lung or breathing problems like asthma, trouble breathing, or sleep apnea; high levels of carbon dioxide in the blood; or stomach or bowel block or narrowing.
  • If you have a long QT on ECG.
  • If you are taking any of these drugs: Buprenorphine, butorphanol, nalbuphine, or pentazocine.
  • If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for Parkinson’s disease like selegiline or rasagiline in the last 14 days. Taking this drug within 14 days of those drugs can cause very bad high blood pressure.
  • If you are taking any of these drugs: Linezolid or methylene blue.
  • If you are breast-feeding. Do not breast-feed while you take this drug.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • All products:
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this drug affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • This drug may raise the chance of seizures in some people, including people who have had seizures in the past. Talk to your doctor to see if you have a greater chance of seizures while taking this drug.
  • Certain strengths of this drug may only be used by people who have been taking drugs like this drug and are used to their effects. The use of these strengths by people who have not been taking drugs like this drug may cause very bad and sometimes deadly breathing problems. Talk with the doctor.
  • Do not take this drug with other strong pain drugs or if you are using a pain patch without talking to your doctor first.
  • If you have been taking this drug for a long time or at high doses, it may not work as well and you may need higher doses to get the same effect. This is known as tolerance. Call your doctor if this drug stops working well. Do not take more than ordered.
  • Do not stop taking this drug all of a sudden without calling your doctor. You may have a greater risk of signs of withdrawal. If you need to stop this drug, you will want to slowly stop it as ordered by your doctor.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • This drug may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this drug, call your doctor right away.
  • Extended-release tablets:
  • The chance of the tablet getting stuck in the throat, trouble swallowing, and choking may be raised in children. Talk with the doctor.
What are some side effects that I need to call my doctor about right away?
  • 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:
  • All products:
  • 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.
  • Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal.
  • Very bad dizziness or passing out.
  • Chest pain or pressure.
  • Trouble breathing, slow breathing, or shallow breathing.
  • Swelling in the arms or legs.
  • A burning, numbness, or tingling feeling that is not normal.
  • A fast heartbeat.
  • Feeling confused.
  • Very bad constipation.
  • Very bad belly pain.
  • Feeling very tired or weak.
  • Mood changes.
  • Very bad headache.
  • Memory problems or loss.
  • Pain when passing urine.
  • Seizures.
  • A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take this drug with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
  • Taking an opioid drug like this drug may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.
  • Long-term use of an opioid drug like this drug may lead to lower sex hormone levels. This may lead to signs like change in sex ability in men, no menstrual period in women, lowered interest in sex, or fertility problems. Call your doctor if you have any of these signs.
  • Extended-release tablets:
  • Choking.
  • Trouble swallowing.
What are some other side effects of this drug?
  • 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:
  • Constipation.
  • Feeling sleepy.
  • Upset stomach or throwing up.
  • Feeling tired or weak.
  • Belly pain.
  • Headache.
  • Dizziness.
  • Signs of a common cold.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • All products:
  • Take by mouth only.
  • Take with or without food. Take with food if it causes an upset stomach.
  • To gain the most benefit, do not miss doses.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • Take this drug at the same time of day.
  • Do not inject or snort this drug. Doing any of these things can cause very bad side effects like trouble breathing and death from overdose.
  • Do not use for fast pain relief or on an as needed basis.
  • Do not use for pain relief after surgery if you have not been taking drugs like this drug.
  • Do not use more than what your doctor told you to use. Do not use more often or longer than what you were told. Doing any of these things may raise the chance of very bad side effects.
  • If you have trouble swallowing, talk with your doctor.
  • Extended-release capsules:
  • Swallow whole. Do not crush, chew, or dissolve the capsule or its contents.
  • Take 1 capsule at a time if your dose is more than 1 capsule. Swallow the capsule with lots of water right after putting it in your mouth.
  • Extended-release tablets:
  • Swallow whole. Do not chew, break, or crush.
  • Take 1 tablet at a time if your dose is more than 1 tablet. Do not lick or wet the tablet before putting it in your mouth. Swallow the tablet with lots of water right after putting it in your mouth.
What do I do if I miss a dose?
  • Skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Hydrocodone and Acetaminophen (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(hye droe KOE done & a seet a MIN oh fen)

Brand Names: US

hycet [DSC]; Lorcet; Lorcet HD; Lorcet Plus; Lortab; Norco; Verdrocet; Vicodin; Vicodin ES; Vicodin HP; Xodol 10/300; Xodol 5/300; Xodol 7.5/300; Zamicet [DSC]

Warning
  • All products:
  • This drug may be habit-forming with long-term use.
  • This drug is a strong pain drug that can put your child at risk for addiction, abuse, and misuse. Misuse or abuse of this drug can lead to overdose and death. Talk with your child’s doctor.
  • Your child will be watched closely to make sure your child does not misuse, abuse, or become addicted to this drug.
  • This drug may cause very bad and sometimes deadly breathing problems. Call the doctor right away if your child has slow, shallow, or trouble breathing.
  • The chance of very bad and sometimes deadly breathing problems may be greater when your child first starts this drug or anytime the dose is raised. Talk with your child’s doctor.
  • Even one dose of this drug may be deadly if it is taken by someone else or by accident, especially in children. If this drug is taken by someone else or by accident, get medical help right away.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • This drug has an opioid drug in it. The use of opioid drugs along with a benzodiazepine drug or other drugs that may make you drowsy or slow your actions has led to very bad side effects. Side effects that have happened include slowed or trouble breathing and deaths. Benzodiazepine drugs include drugs like alprazolam, diazepam, and lorazepam. Benzodiazepine drugs are used to treat many health problems like anxiety, trouble sleeping, or seizures. Talk with the doctor.
  • Many other drugs interact with this drug. These drugs can raise the chance of side effects as well as very bad and sometimes deadly breathing problems. Talk with the doctor and pharmacist to make sure that it is safe for your child to use this drug with all of his/her other drugs.
  • Be sure your child does not drink alcohol or use products that have alcohol. Unsafe and sometimes deadly effects may happen.
  • Get medical help right away if your child does not respond, answer, or react like normal; feels very sleepy or dizzy; passes out; or will not wake up.
  • This drug has acetaminophen in it. Liver problems have happened with the use of acetaminophen. Sometimes, this has led to a liver transplant or death. Most of the time, liver problems happened in people taking too much acetaminophen in a day. People were also often taking more than 1 drug that had acetaminophen in it. If you have questions, talk with your child’s doctor.
  • If your child is pregnant:
  • Using this drug for a long time during pregnancy may lead to withdrawal in the newborn baby. This can be life-threatening. Talk with the doctor.
  • Liquid:
  • Be sure that you know how to measure your child’s dose. Dosing errors can lead to accidental overdose and death. If you have any questions, talk with your child’s doctor or pharmacist.
What is this drug used for?
  • It is used to ease pain.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to this drug or any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child has any of these health problems: Lung or breathing problems like asthma, trouble breathing, or sleep apnea; high levels of carbon dioxide in the blood, or stomach or bowel block or narrowing.
  • If your child is taking any of these drugs: Buprenorphine, butorphanol, nalbuphine, or pentazocine.
  • If your child has taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for certain other health problems in the last 14 days. Taking this drug within 14 days of those drugs can cause very bad high blood pressure.
  • If your child is taking any of these drugs: Linezolid or methylene blue.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • Have your child avoid tasks or actions that call for alertness until you see how this drug affects your child. These are things like riding a bike, playing sports, or using items such as scissors, lawnmowers, electric scooters, toy cars, or motorized vehicles.
  • To lower the chance of feeling dizzy or passing out, have your child rise slowly if your child has been sitting or lying down. Have your child be careful going up and down stairs.
  • Allergic reactions have happened with this drug. Rarely, some reactions can be very bad or life-threatening. Talk with the doctor.
  • Do not give this drug with other strong pain drugs or pain patches without talking to your child’s doctor first.
  • This drug may affect certain lab tests. Tell all of your child’s health care providers and lab workers that your child takes this drug.
  • If your child has been taking this drug for a long time or at high doses, it may not work as well and your child may need higher doses to get the same effect. This is known as tolerance. Call the doctor if this drug stops working well. Do not give more than ordered.
  • If your child has been taking this drug on a regular basis and stops taking it all of a sudden, your child may have signs of withdrawal. Do not stop giving this drug all of a sudden without calling the doctor. Tell the doctor if your child has any bad effects.
  • Avoid giving your child other products that have acetaminophen in them. Check labels closely. Too much acetaminophen may cause liver problems.
  • Follow the directions exactly. Do not give your child more acetaminophen in a day than directed. If you do not know how much acetaminophen you can give to your child in a day, ask your child’s doctor or pharmacist. Call your child’s doctor right away if you have given your child too much acetaminophen in a day, even if your child feels well.
  • Long-term use of an opioid drug like this drug may lead to lower sex hormone levels. This may lead to signs like change in sex ability in males, no menstrual period in females, lowered interest in sex, or fertility problems. If any of these apply to your child, call your child’s doctor.
  • This drug may raise the chance of seizures in some people, including people who have had seizures in the past. Talk to the doctor to see if your child has a greater chance of seizures while taking this drug.
  • Use with care in children. Talk with the doctor.
  • If your child is pregnant or breast-feeding a baby:
  • This drug may cause harm to the unborn baby if your child takes it during pregnancy. If your child is pregnant or gets pregnant while taking this drug, call the doctor right away.
  • Tell your child’s doctor if your child is breast-feeding a baby. This drug passes into breast milk and may harm your child’s baby.
What are some side effects that I need to call my child’s doctor about right away?
  • 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 child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • 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.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Very bad dizziness or passing out.
  • Feeling very sleepy.
  • Trouble breathing, slow breathing, or shallow breathing.
  • Feeling confused.
  • Trouble walking.
  • Feeling very tired or weak.
  • Very bad constipation.
  • Very bad belly pain.
  • Not able to pass urine or change in how much urine is passed.
  • Hearing loss.
  • Change in hearing.
  • Chest pain or pressure or a fast heartbeat.
  • Fever or chills.
  • Sore throat.
  • Mood changes.
  • Very bad headache.
  • Trouble passing urine.
  • Any unexplained bruising or bleeding.
  • Change in eyesight.
  • Seizures.
  • A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if your child has signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in the mouth, throat, nose, or eyes.
  • A very bad and sometimes deadly health problem called serotonin syndrome may happen if your child takes this drug with drugs for depression, migraines, or certain other drugs. Call the doctor right away if your child has agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
  • Taking an opioid pain drug like this drug may lead to a rare but very bad adrenal gland problem. Call your child’s doctor right away if your child has very bad dizziness or passing out, very bad upset stomach or throwing up, or if your child feels less hungry, very tired, or very weak.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if any of these side effects or any other side effects bother your child or do not go away:
  • Upset stomach or throwing up.
  • Constipation.
  • Dizziness.
  • Feeling sleepy.
  • Feeling tired or weak.
  • Headache.
  • Belly pain.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • All products:
  • Give this drug with or without food. Give with food if it causes an upset stomach.
  • Liquid:
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.
  • Do not use a household teaspoon or tablespoon to measure this drug. Doing so could lead to the dose being too high.
What do I do if my child misses a dose?
  • If your child takes this drug on a regular basis, give a missed dose as soon as you think about it.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
  • Many times this drug is given on an as needed basis. Do not give to your child more often than told by the doctor.
How do I store and/or throw out this drug?
  • Tablets and capsules:
  • Store at room temperature.
  • Liquid:
  • Store at room temperature. Do not refrigerate or freeze.
  • All products:
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your child’s doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.