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    Opioid Antitussive and Expectorant Combinations

    BOXED WARNING

    Alcoholism, depression, substance abuse

    Hydrocodone is an opioid agonist and therefore has abuse potential and a risk for fatal overdose from depressed respiration. Consuption of hydrocodone with ethanol will result in additive central nervous system (CNS) and respiratory depressant effects. Patients with alcoholism should be advised of this serious risk, or an alternative medication should be used. Addiction may occur in patients who obtain hydrocodone illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. Patients with an individual or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. To discourage abuse, reserve guaifenesin; hydrocodone for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Prescribe the smallest appropriate quantity for the shortest duration that is consistent with individual treatment goals. Proper disposal instructions for unused drug should be given to patients; refill only after reevaluation of the need for continued treatment.

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, coma, cor pulmonale, hypoxemia, neuromuscular disease, obesity, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    Guaifenesin; hydrocodone is contraindicated for use in patients with significant respiratory depression and in patients with acute or severe asthma (e.g., status asthmaticus) in unmonitored care settings or in the absence of resuscitative equipment. Receipt of moderate hydrocodone doses in these patients may significantly decrease pulmonary ventilation. Additionally, avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Opioid analgesics and antitussives, including hydrocodone should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function. In patients with chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, neuromuscular disease, or preexisting respiratory depression, it is recommended that non-opioid antitussives be considered as alternatives to hydrocodone, as even usual therapeutic doses of hydrocodone may decrease respiratory drive and cause apnea in these patient populations. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, or paralysis of the phrenic nerve. Patients with advanced age, debilitation, or sleep apnea are at an increased risk for the development of respiratory depression associated with hydrocodone. Use with caution in patients with obesity as this is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Concomitant use of guaifenesin; hydrocodone with CYP3A4 inhibitors or inducers, or CYP2D6 inhibitors should be avoided; concurrent use of a CYP3A4 or CYP2D6 inhibitor or discontinuation of a concurrently used CYP3A4 inducer may increase plasma hydrocodone concentrations and potentiate the risk of fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing of guaifenesin; hydrocodone is essential. Monitor patients closely, especially within the first 24 to 72 hours of initiating therapy or when used in patients at higher risk. An unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease. Management of respiratory depression should include observation, necessary supportive measures, and opioid antagonist use when indicated.

    Accidental exposure, ethanol ingestion, ethanol intoxication, potential for overdose or poisoning

    Like all opioid analgesics, hydrocodone is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Ensure accuracy when prescribing, dispensing, and administering guaifenesin; hydrocodone cough products as dosing errors can result in accidental overdose and death. Guaifenesin; hydrocodone should be kept out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets, as accidental exposure of even 1 dose of hydrocodone may cause respiratory failure and a fatal overdose. Ethanol ingestion with these products may result in increased plasma levels and a potentially fatal overdose of hydrocodone. Consumption of ethanol with hydrocodone will result in additive CNS depressant effects which may lead to respiratory depression; ethanol intoxication must be avoided. Advise patients to avoid alcohol ingestion including the ingestion of alcohol contained in prescription or non-prescription medications, during therapy.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    There are no data or data are insufficient to inform a drug-associated risk for major birth defects or miscarriage with guaifenesin; hydrocodone use as an antitussive in human pregnancy. In animal studies, hydrocodone administered to pregnant rats during organogenesis, gestation, or lactation resulted in decreased body weight of offspring, reduced nursing behavior, increased post-implantation loss, and non-viable litters at doses approximately 2- to 3-fold human hydrocodone doses of 100 to 180 mg/day; decreases in survival were seen in the offspring of rats given hydrocodone during gestation and lactation at doses equivalent to a human dose of 180 mg/day and above. Fetal malformations including increases in umbilical hernias, irregularly shaped bones, and delays in fetal skeletal maturation occurred with doses equivalent to 15 times an adult human dose of 100 mg/day. Guaifenesin; hydrocodone is not recommended for use in women during and immediately prior to labor and obstetric delivery because opioid agonists may cause respiratory depression in the newborn. Opioid analgesics can prolong labor by reducing the strength and frequency of uterine contractions; however, this effect may be offset by an increased rate of cervical dilation. Further, prolonged maternal use of long-acting opioids, such as hydrocodone, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

    DEA CLASS

    Rx, schedule II

    DESCRIPTION

    Hydrocodone is an opiate agonist antitussive agent; guaifenesin is an expectorant
    Used to treat cough
    Not indicated in pediatric patients under 18 years of age; contraindicated in neonates, infants and children less than 6 years of age

    COMMON BRAND NAMES

    Flowtuss, OBREDON

    HOW SUPPLIED

    Hydrocodone Bitartrate, Guaifenesin/OBREDON Oral Liq: 5mL, 2.5-200mg

    DOSAGE & INDICATIONS

    For the symptomatic treatment of cough and to loosen mucus associated with the common cold.
    Oral dosage (oral solutions or syrups with hydrocodone 2.5 mg and guaifenesin 200 mg per 5 mL, e.g., Obredon)
    Adults

    10 mL (containing 5 mg hydrocodone with 400 mg guaifenesin per 10 mL) PO every 4 to 6 hours as needed, not to exceed 6 doses (60 mL) in 24 hours. LIMITATION OF USE: Reserve guaifenesin; hydrocodone for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Prescribe for the shortest duration consistent with individual patient treatment goals. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy; proper dosing is essential to reduce the risk of respiratory depression. Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease. CONTINUED TREATMENT: If a patient requires a refill, reevaluate the cause of the cough and the need for continued treatment. DISCONTINUATION: Do not abruptly discontinue this product in a physically-dependent patient; taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If withdrawal occurs, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

    MAXIMUM DOSAGE

    Adults

    30 mg/day hydrocodone PO; 2.4 g/day guaifenesin PO.

    Geriatric

    30 mg/day hydrocodone PO; 2.4 g/day guaifenesin PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    6 to 12 years: Safety and efficacy have not been established.
    Less than 6 years: Use is contraindicated.

    Infants

    Use is contraindicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific dose adjustment recommendations are not available; decreased elimination of hydrocodone can occur. Use with caution in patients with severe hepatic impairment, and monitor closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension). Based on recommendations for some analgesic products containing hydrocodone, consider an initial reduction in hydrocodone dosage of 50% for patients with hepatic impairment.

    Renal Impairment

    Specific dose adjustment recommendations are not available; however, deceased elimination of hydrocodone can occur. Use with caution in patients with moderate to severe renal impairment, and monitor closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension). Based on recommendations for some analgesic products containing hydrocodone, consider an initial reduction in hydrocodone dosage of 50% for patients with moderate to severe renal impairment.

    ADMINISTRATION

    Oral Administration

    Administer with a full glass of water. May take with food or milk to minimize GI irritation.
    Cough preparations should not be administered more frequently than prescribed; do not administer more frequently than recommended or prescribed as severe, possibly fatal, respiratory depression may occur.
    An unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease.

    Oral Liquid Formulations

    Advise patients/caregivers to use a calibrated oral syringe, spoon or other proper measuring device. Do not to overfill.
    Rinse the measuring device with water after each use.

    STORAGE

    A-COF DH :
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Atuss HX:
    - Store at room temperature (between 59 to 86 degrees F)
    Canges-XP:
    - Store at room temperature (between 59 to 86 degrees F)
    Cleartuss DH:
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Codiclear DH:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Condasin:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Cotuss-V:
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    EndaCof-Tab:
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    EndaCof-XP :
    - Store at room temperature (between 59 to 86 degrees F)
    ExeClear :
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    ExeCof-XP:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    Extendryl HC:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Fentuss Expectorant:
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Flowtuss:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    FluTuss XP:
    - Store at room temperature (between 59 to 86 degrees F)
    G-Tuss :
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Hycosin Expectorant :
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Hycotuss:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Hydro-Tuss:
    - Storage information not listed
    Hydro-Tussin HG:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Kwelcof :
    - Storage information not listed
    M-Clear:
    - Storage information not listed
    Medcodin :
    - Storage information not listed
    Narcof:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    OBREDON:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Pancof XP:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    Pneumotussin:
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    Pneumotussin HC:
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Relasin-HCX:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Touro HC:
    - Store at room temperature (between 59 to 86 degrees F)
    Tussiclear DH :
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tusso-DF:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    Tusso-HC:
    - Store at room temperature (between 59 to 86 degrees F)
    Vicoclear DH :
    - Storage information not listed
    Vicodin Tuss:
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    VI-Q-Tuss :
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vitussin :
    - Protect from freezing
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Xpect-HC:
    - Store at room temperature (between 59 to 86 degrees F)
    Z-Cof HCX:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    ZTuss ZT:
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Opiate agonist hypersensitivity

    Although true opiate agonist hypersensitivity is rare, the use of hydrocodone is contraindicated in patients who have hypersensitivity to hydrocodone, guaifenesin, or any of the inactive ingredients in product. Patients who have demonstrated a prior hypersensitivity reaction to guaifenesin; hydrocodone should not receive other opioid agonists of the phenanthrene subclass including oxycodone, codeine and morphine. It is possible to treat these patients with an opioid agonist from the phenylpiperidine subclass (meperidine or fentanyl) or the diphenylheptane subclass (methadone).

    Alcoholism, depression, substance abuse

    Hydrocodone is an opioid agonist and therefore has abuse potential and a risk for fatal overdose from depressed respiration. Consuption of hydrocodone with ethanol will result in additive central nervous system (CNS) and respiratory depressant effects. Patients with alcoholism should be advised of this serious risk, or an alternative medication should be used. Addiction may occur in patients who obtain hydrocodone illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. Patients with an individual or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. To discourage abuse, reserve guaifenesin; hydrocodone for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Prescribe the smallest appropriate quantity for the shortest duration that is consistent with individual treatment goals. Proper disposal instructions for unused drug should be given to patients; refill only after reevaluation of the need for continued treatment.

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, coma, cor pulmonale, hypoxemia, neuromuscular disease, obesity, pulmonary disease, respiratory depression, respiratory insufficiency, scoliosis, sleep apnea, status asthmaticus

    Guaifenesin; hydrocodone is contraindicated for use in patients with significant respiratory depression and in patients with acute or severe asthma (e.g., status asthmaticus) in unmonitored care settings or in the absence of resuscitative equipment. Receipt of moderate hydrocodone doses in these patients may significantly decrease pulmonary ventilation. Additionally, avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Opioid analgesics and antitussives, including hydrocodone should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function. In patients with chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, neuromuscular disease, or preexisting respiratory depression, it is recommended that non-opioid antitussives be considered as alternatives to hydrocodone, as even usual therapeutic doses of hydrocodone may decrease respiratory drive and cause apnea in these patient populations. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, or paralysis of the phrenic nerve. Patients with advanced age, debilitation, or sleep apnea are at an increased risk for the development of respiratory depression associated with hydrocodone. Use with caution in patients with obesity as this is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Concomitant use of guaifenesin; hydrocodone with CYP3A4 inhibitors or inducers, or CYP2D6 inhibitors should be avoided; concurrent use of a CYP3A4 or CYP2D6 inhibitor or discontinuation of a concurrently used CYP3A4 inducer may increase plasma hydrocodone concentrations and potentiate the risk of fatal respiratory depression. To reduce the risk of respiratory depression, proper dosing of guaifenesin; hydrocodone is essential. Monitor patients closely, especially within the first 24 to 72 hours of initiating therapy or when used in patients at higher risk. An unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease. Management of respiratory depression should include observation, necessary supportive measures, and opioid antagonist use when indicated.

    Brain tumor, head trauma, increased intracranial pressure

    Avoid the use of guaifenesin; hydrocodone in patients with head trauma, intracranial lesions, or pre-existing increased intracranial pressure. In patients who may be susceptible to the intracranial effects of carbon dioxide (CO2) retention (e.g., those with evidence of increased intracranial pressure or brain tumor), guaifenesin; hydrocodone may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

    Accidental exposure, ethanol ingestion, ethanol intoxication, potential for overdose or poisoning

    Like all opioid analgesics, hydrocodone is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Ensure accuracy when prescribing, dispensing, and administering guaifenesin; hydrocodone cough products as dosing errors can result in accidental overdose and death. Guaifenesin; hydrocodone should be kept out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets, as accidental exposure of even 1 dose of hydrocodone may cause respiratory failure and a fatal overdose. Ethanol ingestion with these products may result in increased plasma levels and a potentially fatal overdose of hydrocodone. Consumption of ethanol with hydrocodone will result in additive CNS depressant effects which may lead to respiratory depression; ethanol intoxication must be avoided. Advise patients to avoid alcohol ingestion including the ingestion of alcohol contained in prescription or non-prescription medications, during therapy.

    Driving or operating machinery

    Any patient receiving guaifenesin; hydrocodone should be warned about the possibility of sedation and to use caution when driving or operating machinery. Hydrocodone may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of guaifenesin; hydrocodone. Avoid concurrent use of this cough product with alcohol or other CNS depressants because additional impairment of central nervous system performance may occur.

    Abrupt discontinuation

    Guaifenesin; hydrocodone is not intended for prolonged use for cough. Abrupt discontinuation of prolonged hydrocodone therapy can result in withdrawal symptoms. Gradually reduce the dose to prevent signs and symptoms of withdrawal in the physically-dependent patient. Avoid use of partial agonists (e.g., buprenorphine), mixed agonist/antagonists (e.g., nalbuphine), or pure antagonists (e.g., naloxone) in patients physically dependent on opioids, as an acute withdrawal syndrome may precipitate. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and on the administered dose of the concomitant drug. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. In addition, the use of partial agonists or mixed agonist/antagonists in patients who have received or are receiving hydrocodone should be avoided as these medications may reduce the analgesic effect of hydrocodone.

    Cardiac disease, dehydration, hypotension, hypovolemia, orthostatic hypotension, shock, syncope

    Guaifenesin; hydrocodone may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume (hypovolemia or dehydration) or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Also use with caution in patients with significant cardiac disease. Monitor these patients for signs of hypotension after initiating guaifenesin; hydrocodone. In patients with circulatory shock, hydrocodone may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of guaifenesin; hydrocodone in patients with circulatory shock.

    Acute abdomen, constipation, diarrhea, GI disease, GI obstruction, ileus, inflammatory bowel disease, ulcerative colitis

    Guaifenesin; hydrocodone is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. Due to the effects of opiate agonists on the gastrointestinal tract, guaifenesin; hydrocodone should be used cautiously in patients with GI disease, such as ulcerative colitis (UC). Patients with UC or other inflammatory bowel disease may be more sensitive to constipation caused by opioid agonists. Opioid agonists may obscure the diagnosis or clinical course in patients with acute abdomen. Although opiate agonists are contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opiate agonists should not be given until the toxic substance has been eliminated.

    Biliary tract disease, gallbladder disease, pancreatitis

    Hydrocodone should be used with caution in patients with biliary tract disease, such as acute pancreatitis and gallbladder disease. As with other opioid agonists, hydrocodone may cause spasm of the sphincter of Oddi, increasing biliary tract pressure. Biliary effects due to opiate agonists have resulted in an increase in plasma amylase and lipase concentrations up to 2 to 15 times the normal values; determination of these enzyme levels may be unreliable for 24 hours after administration.

    Hepatic disease

    Guaifenesin; hydrocodone should be used with caution in patients with severe hepatic disease, and patients should be monitored closely for respiratory depression, sedation, and hypotension. Patients with severe hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal hepatic function. In acute situations, these patients require close monitoring to avoid excessive toxicity. Patients with chronic liver disease may require less frequent dosing intervals.

    Renal failure, renal impairment

    Guaifenesin; hydrocodone should be used with caution in patients with severe renal impairment or renal failure, and these patients should be monitored closely for respiratory depression, sedation, and hypotension. Hydrocodone accumulation or prolonged duration of action can occur in patients with severe renal impairment. In acute situations, such patients require close monitoring to avoid excessive toxicity. Patients with chronic renal disease may require less frequent dosing intervals.

    Bladder obstruction, prostatic hypertrophy, urethral stricture, urinary retention

    Hydrocodone may cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to urinary tract effects include those patients with prostatic hypertrophy, urethral stricture, bladder obstruction, or pelvic tumors. The concomitant use of anticholinergic drugs with guaifenesin; hydrocodone may increase risk of urinary retention.

    Seizure disorder, seizures

    Hydrocodone may increase the frequency of seizures in patients with a seizure disorder, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during guaifenesin; hydrocodone therapy.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use guaifenesin; hydrocodone with caution in patients with Addison's disease or other conditions of adrenal insufficiency. Cases of adrenal insufficiency have been reported with opioid use, more often following more than 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH). Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients should seek immediate medical attention if they experience symptoms of adrenocortical insufficiency. Chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Male patients with signs or symptoms of androgen deficiency should undergo evaluation. Patients with hypothyroidism or myxedema should also receive opioid therapy with caution, as thyroid stimulating hormone (TSH) may be either stimulated or inhibited by opioids.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    There are no data or data are insufficient to inform a drug-associated risk for major birth defects or miscarriage with guaifenesin; hydrocodone use as an antitussive in human pregnancy. In animal studies, hydrocodone administered to pregnant rats during organogenesis, gestation, or lactation resulted in decreased body weight of offspring, reduced nursing behavior, increased post-implantation loss, and non-viable litters at doses approximately 2- to 3-fold human hydrocodone doses of 100 to 180 mg/day; decreases in survival were seen in the offspring of rats given hydrocodone during gestation and lactation at doses equivalent to a human dose of 180 mg/day and above. Fetal malformations including increases in umbilical hernias, irregularly shaped bones, and delays in fetal skeletal maturation occurred with doses equivalent to 15 times an adult human dose of 100 mg/day. Guaifenesin; hydrocodone is not recommended for use in women during and immediately prior to labor and obstetric delivery because opioid agonists may cause respiratory depression in the newborn. Opioid analgesics can prolong labor by reducing the strength and frequency of uterine contractions; however, this effect may be offset by an increased rate of cervical dilation. Further, prolonged maternal use of long-acting opioids, such as hydrocodone, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

    Breast-feeding

    Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a nursing infant, advise patients that breast-feeding is not recommended during treatment with guaifenesin; hydrocodone. Consider alternative treatments for cough in the breast-feeding mother. Hydrocodone is distributed into breast milk at varying degrees depending upon the dose. A pharmacokinetic study in 30 women receiving hydrocodone for postpartum pain found that breast-fed newborns (postnatal age 3 to 11 days) received a median of 1.6% (range 0.2% to 9%) of the maternal weight-adjusted hydrocodone dosage. The total opiate dosage via breast milk, including the active metabolite hydromorphone, was found to be 0.7% of a therapeutic dosage used for an older infant. The authors concluded that doses of hydrocodone given to breast-feeding mothers should be limited to 30 mg/day and doses higher than 40 mg/day should be avoided.

    Children, infants, neonates

    Opioid cough and cold medicines that contain hydrocodone, such as guaifenesin; hydrocodone, are not indicated for pediatric patients under 18 years of age. These products are contraindicated in neonates, infants, and children less than 6 years of age. The use of hydrocodone in children younger than 6 years of age has been associated with fatal respiratory depression when used as recommended. Risks of these medicines outweigh their benefits in patients younger than 18 years. Such risks include slowed or difficult breathing, misuse, abuse, addiction, overdose, and death.

    Dementia, geriatric

    Use guaifenesin; hydrocodone with caution in geriatric patients or debilitated patients. Geriatric or debilitated patients are more susceptible to adverse reactions from opiate agonists; especially sedation and respiratory depression probably as a result of altered distribution of the drug and decreased elimination. Initial doses of opiate agonists may need to be reduced and doses should be carefully titrated taking into account clinical goals, adverse reactions, and concomitant drugs that may depress respiration. Use particular care in using opiate-based antitussive agents in geriatric patients with dementia/cognitive impairment who may have increase risk for CNS depression and respiratory insufficiency. According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these populations, with the exception of pain management due to recent fractures or joint replacement, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, cough, cold, and allergy medications should be used only for a limited duration (less than 14 days) unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known
    cyanosis / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    pulmonary edema / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    GI obstruction / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    biliary obstruction / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    neonatal opioid withdrawal syndrome / Delayed / Incidence not known
    neonatal respiratory depression / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 10.0
    psychological dependence / Delayed / 10.0
    physiological dependence / Delayed / 10.0
    dyskinesia / Delayed / Incidence not known
    euphoria / Early / Incidence not known
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    dysphoria / Early / Incidence not known
    hallucinations / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    migraine / Early / Incidence not known
    impaired cognition / Early / Incidence not known
    wheezing / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    dysphagia / Delayed / Incidence not known
    hyperamylasemia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    hot flashes / Early / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    bladder spasm / Early / Incidence not known
    blurred vision / Early / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    tolerance / Delayed / Incidence not known

    Mild

    lethargy / Early / 1.0-10.0
    headache / Early / 1.0-10.0
    drowsiness / Early / 10.0
    dizziness / Early / 10.0
    xerostomia / Early / 10.0
    vertigo / Early / Incidence not known
    tremor / Early / Incidence not known
    emotional lability / Early / Incidence not known
    fatigue / Early / Incidence not known
    restlessness / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    tinnitus / Delayed / Incidence not known
    psychomotor impairment / Early / Incidence not known
    agitation / Early / Incidence not known
    insomnia / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    bronchial secretions / Early / Incidence not known
    nasal dryness / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    nausea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    dyspepsia / Early / Incidence not known
    vomiting / Early / Incidence not known
    syncope / Early / Incidence not known
    infection / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    miosis / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abiraterone: (Moderate) Concomitant use of hydrocodone with abiraterone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of abiraterone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If abiraterone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Abiraterone is a moderate inhibitor of CYP2D6.
    Acetaminophen; Butalbital: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Acetaminophen; Butalbital; Caffeine: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Codeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Concomitant use of hydrocodone with other central nervous system depressants can potentiate the effects of hydrocodone and may lead to additive CNS or respiratory depression. If hydrocodone is used with a CNS depressant, the dose of one or both drugs should be reduced.
    Acetaminophen; Diphenhydramine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Oxycodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as hydrocodone. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of hydrocodone. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Propoxyphene: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Tramadol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
    Acrivastine; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity such as opiate agonists. In addition, aldesleukin, IL-2, is a CYP3A4 inhibitor and may increase oxycodone plasma concentrations and related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patients for an extended period and adjust oxycodone dosage as necessary.
    Alfentanil: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Aliskiren; Amlodipine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Almotriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering serotonin-receptor agonists with other drugs that have serotonergic properties such as opioids. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Alosetron: (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alprazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Aluminum Hydroxide; Magnesium Hydroxide: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as magnesium hydroxide, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as magnesium hydroxide, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Amide local anesthetics: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amifampridine: (Moderate) Carefully consider the need for concomitant treatment with opioid agonists and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Opioid agonists may increase the risk of seizures.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amiodarone: (Moderate) Concomitant use of hydrocodone with amiodarone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of amiodarone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If amiodarone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Amiodarone is an inhibitor of CYP3A4 and CYP2D6.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Amlodipine: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Amlodipine; Benazepril: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amlodipine; Olmesartan: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Amlodipine; Telmisartan: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Amlodipine; Valsartan: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with amlodipine is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If amlodipine is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Amobarbital: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Amoxapine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include amoxapine,
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apalutamide: (Moderate) Concomitant use of hydrocodone with apalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If apalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and hydrocodone could result in additive depressant effects.
    Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
    Aprepitant, Fosaprepitant: (Moderate) Concomitant use of hydrocodone with oral, multi-day regimens of aprepitant may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of aprepitant could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If aprepitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor.
    Armodafinil: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with armodafinil is necessary; consider increasing the dose of hydrocodone as needed. If armodafinil is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and armodafinil is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Artemether; Lumefantrine: (Moderate) Concomitant use of hydrocodone with artemether; lumefantrine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of artemether; lumefantrine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If artemether; lumefantrine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Artemether; lumefantrine is a moderate inhibitor of CYP2D6.
    Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including opiate agonists.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Aspirin, ASA; Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor patients for sedation and respiratory depression.
    Atazanavir: (Moderate) Concomitant use of hydrocodone with atazanavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of atazanavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Atazanavir is a strong inhibitor of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Concomitant use of hydrocodone with atazanavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of atazanavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with cobicistat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cobicistat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cobicistat is a strong inhibitor of CYP3A4 and also inhibits CYP2D6.
    Atenolol; Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Atracurium: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Atropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Difenoxin: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Diphenoxylate: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Edrophonium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azilsartan; Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Baclofen: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Barbiturates: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Belladonna; Opium: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Bendroflumethiazide; Nadolol: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benzonatate: (Moderate) The vagal effects and respiratory depression induced by hydrocodone may be increased by the use of benzonatate.
    Benztropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bethanechol: (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
    Bexarotene: (Moderate) Concomitant use of hydrocodone with bexarotene can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bexarotene is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
    Bisacodyl: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as bisacodyl, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Boceprevir: (Major) Monitor for respiratory depression and sedation if hydrocodone and boceprevir are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as boceprevir, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Bosentan: (Moderate) Concomitant use of hydrocodone with bosentan can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If bosentan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including opiate agonists.
    Brigatinib: (Moderate) Concomitant use of hydrocodone with brigatinib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and in vitro data suggest brigatinib is a CYP3A4 inducer.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brompheniramine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Buprenorphine; Naloxone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as hydrocodone. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone.
    Bupropion: (Moderate) Concomitant use of hydrocodone with bupropion may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of bupropion could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If bupropion is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Bupropion is a strong inhibitor of CYP2D6.
    Bupropion; Naltrexone: (Major) The opiate antagonists naloxone and naltrexone are pharmacologic opposites of hydrocodone. These drugs can block the actions of hydrocodone and, if administered to patients who have received chronic hydrocodone, can produce acute withdrawal and/or reduce the analgesic effect of hydrocodone. (Moderate) Concomitant use of hydrocodone with bupropion may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of bupropion could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If bupropion is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Bupropion is a strong inhibitor of CYP2D6.
    Buspirone: (Moderate) Concomitant use of hydrocodone with other central nervous system depressants, such as buspirone, can potentiate the effects of hydrocodone and may lead to additive CNS or respiratory depression. If hydrocodone is used with buspirone, the dose of one or both drugs should be reduced.
    Butabarbital: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Butorphanol: (Major) Avoid the concomitant use of butorphanol and opiate agonists, such as hydrocodone. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of hydrocodone. Butorphanol may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of butorphanol with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Calcium Carbonate; Magnesium Hydroxide: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as magnesium hydroxide, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Cannabidiol: (Moderate) Concomitant use of opioid agonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of opioid agonists with cannabidiol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking cannabidiol, reduce initial dosage and titrate to clinical response. If cannabidiol is initiated in a patient taking hydrocodone, use a lower initial dose of cannabidiol and titrate to clinical response. Educate patients about the risks and symptoms of excessive CNS depression.
    Capsaicin; Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Carbamazepine: (Moderate) Concomitant use of hydrocodone with carbamazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If carbamazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer.
    Carbetapentane; Chlorpheniramine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pyrilamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Carbinoxamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including opiate agonists.
    Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Castor Oil: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as castor oil, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Ceritinib: (Moderate) Concomitant use of hydrocodone with ceritinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ceritinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ceritinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. In vitro data suggests ceritinib is an inhibitor of CYP3A4.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chloramphenicol: (Moderate) Concomitant use of hydrocodone with chloramphenicol may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of chloramphenicol could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If chloramphenicol is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Chloramphenicol is a strong inhibitor of CYP3A4.
    Chlorcyclizine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Chlordiazepoxide; Clidinium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Chloroprocaine: (Minor) Due to the CNS depression potential of all local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Chlorothiazide: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Codeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpromazine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as phenothiazines, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorzoxazone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Cimetidine: (Minor) Concurrent use may increase the adverse effects of hydrocodone, especially if a large cimetidine dose ( more than 600 mg/day) is used or if the patient is not young and healthy. The clinical significance of this interaction is not established. Monitor patients for increased respiratory and CNS depression.
    Cinacalcet: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Cinacalcet is a strong inhibitor of CYP2D6.
    Ciprofloxacin: (Moderate) Concomitant use of hydrocodone with ciprofloxacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ciprofloxacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ciprofloxacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ciprofloxacin is a moderate inhibitor of CYP3A4.
    Cisatracurium: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as citalopram, with other drugs that have serotonergic properties such as codeine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. codeine and citalopram should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Clarithromycin: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Clemastine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Clobazam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, co-administration of hydrocodone and a CYP2D6 inhibitor, such as clobazam, may result in a reduction in the analgesic effect of hydrocodone. Avoid opiate cough medications in patients taking benzodiazepines.
    Clonazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Clopidogrel: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Clozapine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as clozapine, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, combining clozapine with opiate agonists may lead to additive effects on intestinal motility or bladder function.
    Cobicistat: (Moderate) Concomitant use of hydrocodone with cobicistat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cobicistat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cobicistat is a strong inhibitor of CYP3A4 and also inhibits CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Concomitant use of hydrocodone with cobicistat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cobicistat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cobicistat is a strong inhibitor of CYP3A4 and also inhibits CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of hydrocodone with cobicistat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cobicistat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cobicistat is a strong inhibitor of CYP3A4 and also inhibits CYP2D6.
    Codeine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Codeine; Guaifenesin: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Codeine; Promethazine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    COMT inhibitors: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Conivaptan: (Moderate) Concomitant use of hydrocodone with conivaptan may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of conivaptan could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Conivaptan is a strong inhibitor of CYP3A4.
    Crizotinib: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
    Cyclizine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Cyclobenzaprine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Cyclosporine: (Moderate) Concomitant use of hydrocodone with cyclosporine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cyclosporine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cyclosporine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Cyclosporine is a moderate inhibitor of CYP3A4.
    Cyproheptadine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Dabrafenib: (Moderate) Concomitant use of hydrocodone with dabrafenib can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If dabrafenib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer.
    Dacomitinib: (Moderate) Concomitant use of hydrocodone with dacomitinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dacomitinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dacomitinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6.
    Dalfopristin; Quinupristin: (Moderate) Concomitant use of hydrocodone with dalfopristin; quinupristin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dalfopristin; quinupristin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dalfopristin; quinupristin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Dalfopristin; quinupristin is a weak inhibitor of CYP3A4.
    Danazol: (Moderate) Concomitant use of hydrocodone with danazol may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of danazol could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If danazol is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Danazol is a moderate inhibitor of CYP3A4.
    Dantrolene: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Darifenacin: (Moderate) Concomitant use of hydrocodone with darifenacin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including a risk for hypotension, respiratory depression, profound sedation, coma, and death. Avoid use of hydrocodone when it is being used for cough; consider alternative agents for cough treatment. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darifenacin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darifenacin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Darifenacin is a moderate inhibitor of CYP2D6. In addition, the concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Darifenacin has anticholinergic actions that may produce additive effects. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Darunavir: (Moderate) Concomitant use of hydrocodone with darunavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darunavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Darunavir is a strong inhibitor of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Concomitant use of hydrocodone with cobicistat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cobicistat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cobicistat is a strong inhibitor of CYP3A4 and also inhibits CYP2D6. (Moderate) Concomitant use of hydrocodone with darunavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darunavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Darunavir is a strong inhibitor of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Concomitant use of hydrocodone with cobicistat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cobicistat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cobicistat is a strong inhibitor of CYP3A4 and also inhibits CYP2D6. (Moderate) Concomitant use of hydrocodone with darunavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of darunavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Darunavir is a strong inhibitor of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concomitant use of hydrocodone with ritonavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ritonavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Ritonavir is a strong inhibitor of CYP3A4 and also inhibits CYP2D6.
    Deferasirox: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with deferasirox is necessary; consider increasing the dose of hydrocodone as needed. If deferasirox is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and deferasirox is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Delavirdine: (Moderate) Concomitant use of hydrocodone with delavirdine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of delavirdine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If delavirdine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Delavirdine is a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2D6.
    Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including opiate agonists. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and desvenlafaxine because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with desvenlafaxine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of desvenlafaxine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If desvenlafaxine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Desvenlafaxine is a weak inhibitor of CYP2D6.
    Deutetrabenazine: (Major) Concomitant use of opiate agonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with deutetrabenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking deutetrabenazine, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If deutetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking deutetrabenazine.
    Dexamethasone: (Moderate) Concomitant use of hydrocodone with dexamethasone can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If dexamethasone is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and dexamethasone is a moderate CYP3A4 inducer.
    Dexchlorpheniramine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with opiate agonists likely to lead to an enhancement of CNS depression.
    Dexpanthenol: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Dextromethorphan; Quinidine: (Moderate) Concomitant use of hydrocodone with quinidine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of quinidine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If quinidine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Quinidine is a strong inhibitor of CYP2D6.
    Diazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Dicyclomine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Diltiazem: (Moderate) Concomitant use of hydrocodone with diltiazem may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of diltiazem could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If diltiazem is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Diltiazem is a moderate inhibitor of CYP3A4.
    Dimenhydrinate: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Diphenhydramine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Diphenhydramine; Ibuprofen: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Diphenhydramine; Naproxen: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Doxacurium: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as neuromuscular blockers, can potentiate CNS and respiratory depression. A dose reduction of one or both drugs may be warranted.
    Doxylamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Doxylamine; Pyridoxine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Dronabinol: (Moderate) Concomitant use of opiate agonists and other CNS depressants such as dronabinol, THC may result in respiratory depression, CNS depression, and/or hypotension. Prior to concurrent use of opiate agonists in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment is necessary, reduce the dose of 1 or both drugs. When levorphanol is used with dronabinol, reduce the initial levorphanol dose by approximately 50% or more.
    Dronedarone: (Moderate) Concomitant use of hydrocodone with dronedarone may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of dronedarone could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If dronedarone is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Dronedarone is a moderate inhibitor of CYP3A4 and CYP2D6.
    Droperidol: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. According to the manufacturer, ethanol abuse and the use of benzodiazepines and intravenous opiates are risk factors for the development of prolonged QT syndrome in patients receiving droperidol. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Duloxetine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Efavirenz: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Elagolix: (Moderate) Concomitant use of hydrocodone with elagolix can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If elagolix is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer.
    Elbasvir; Grazoprevir: (Moderate) Administering hydrocodone with elbasvir; grazoprevir may result in elevated hydrocodone plasma concentrations. Hydrocodone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering serotonin-receptor agonists with other drugs that have serotonergic properties such as opioids. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Eliglustat: (Moderate) Concomitant use of hydrocodone with eliglustat may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of eliglustat could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If eliglustat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Eliglustat is a moderate inhibitor of CYP2D6.
    Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Opiate agonists are a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of the opiate agonist is possible. Monitor patients for adverse reactions if eltrombopage is administered with an opiate agonist.
    Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as hydrocodone. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Enflurane: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Enzalutamide: (Moderate) Concomitant use of hydrocodone with enzalutamide can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If enzalutamide is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Erythromycin: (Moderate) Concomitant use of hydrocodone with erythromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation oferythromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. Iferythromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Erythromycin is a moderate inhibitor of CYP3A4.
    Erythromycin; Sulfisoxazole: (Moderate) Concomitant use of hydrocodone with erythromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation oferythromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. Iferythromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Erythromycin is a moderate inhibitor of CYP3A4.
    Escitalopram: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and escitalopram because of the potential risk of serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue hydrocodone if serotonin syndrome is suspected. Additionally, concomitant use of hydrocodone with escitalopram may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of escitalopram could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If escitalopram is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Escitalopram is a weak inhibitor of CYP2D6.
    Eslicarbazepine: (Moderate) Concomitant use of hydrocodone with eslicarbazepine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If eslicarbazepine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
    Estazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Eszopiclone: (Moderate) Concomitant use of hydrocodone with eszopiclone may lead to hypotension, profound sedation, coma, respiratory depression and death. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Etomidate: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Etravirine: (Moderate) Concomitant use of hydrocodone with etravirine can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If etravirine is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and etravirine is a moderate CYP3A4 inducer.
    Everolimus: (Moderate) Monitor for an increase in hydrocodone-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary; consider reducing the dose of hydrocodone if clinically appropriate. If everolimus is discontinued, monitor for evidence of opioid withdrawal until stable drug effects are achieved and consider increasing the hydrocodone dose if necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like everolimus can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If everolimus is discontinued, hydrocodone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Fentanyl: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fesoterodine, an anticholinergic drug for overactive bladder. is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Flavoxate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as opiate agonists, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluconazole: (Moderate) Concomitant use of hydrocodone with fluconazole may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluconazole could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Fluconazole is a moderate inhibitor of CYP3A4.
    Fluoxetine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Fluoxetine; Olanzapine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Concomitant use of hydrocodone with other CNS depressants like olanzapine may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking olanzapine, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider using a lower dose of olanzapine. Monitor patients for sedation and respiratory depression.
    Fluphenazine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as phenothiazines, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Flutamide: (Moderate) Hydrocodone is metabolized by CYP3A4. Flutamide, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with flutamide.
    Fluvoxamine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluvoxamine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluvoxamine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluvoxamine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluvoxamine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Fluvoxamine is a moderate inhibitor of CYP3A4. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Fosamprenavir: (Moderate) Concomitant use of hydrocodone with fosamprenavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fosamprenavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fosamprenavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Fosamprenavir is a strong inhibitor of CYP3A4.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Fosphenytoin: (Moderate) Concomitant use of hydrocodone with fosphenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If fosphenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer.
    Fospropofol: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Fostamatinib: (Moderate) Monitor for hydrocodone toxicities that may require hydrocodone dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; hydrocodone is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    Frovatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering serotonin-receptor agonists with other drugs that have serotonergic properties such as opioids. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Gabapentin: (Moderate) Coadministration of gabapentin may decrease the Cmax and AUC of hydrocodone in a dose-dependent manner relative to administration of hydrocodone alone. The mechanism for this interaction is unknown. In addition, hydrocodone may increase gabapentin AUC. Until more information is available, patients should be observed for indications that hydrocodone is not as effective, or for signs of additive drowsiness when these drugs are used together. The dose of gabapentin and/or hydrocodone should be adjusted appropriately if needed.
    Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Glycopyrrolate; Formoterol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering serotonin-receptor antagonists with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and the serotonin-receptor antagonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Grapefruit juice: (Moderate) Patients should not significantly alter their intake of grapefruit or grapefruit juice during therapy with hydrocodone. Grapefruit juice, a CYP3A4 inhibitor, may increase plasma concentrations of hydrocodone, a CYP3A4 substrate. This may increase or prolong hydrocodone-related toxicities including respiratory depression. Advise patients accordingly; patient monitoring and dosage adjustments may be necessary if grapefruit is consumed regularly.
    Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as opiate agonists, when administered concomitantly.
    Guanfacine: (Moderate) Central-acting adrenergic agonists like guanfacine have CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Haloperidol: (Moderate) Concomitant use of hydrocodone with haloperidol may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of haloperidol could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If haloperidol is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Haloperidol is a moderate inhibitor of CYP2D6.
    Halothane: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Homatropine; Hydrocodone: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Opiate agonists like hydrocodone may potentiate orthostatic hypotension when given concomitantly with spironolactone. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydromorphone: (Major) Concomitant use of hydromorphone with other central nervous system (CNS) depressants, such as other opiate agonists like hydrocodone, can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Hydroxychloroquine: (Moderate) Concomitant use of hydrocodone with hydroxychloroquine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of hydroxychloroquine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If hydroxychloroquine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Hydroxychloroquine is a moderate inhibitor of CYP2D6.
    Hydroxyzine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Ibuprofen; Oxycodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor patients for sedation and respiratory depression.
    Idelalisib: (Moderate) Concomitant use of hydrocodone with idelalisib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of idelalisib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If idelalisib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Idelalisib is a strong inhibitor of CYP3A4.
    Iloperidone: (Moderate) Concomitant use of iloperidone with other centrally-acting medications such as opiate agonists, may increase both the frequency and the intensity of adverse effects including drowsiness, sedation, and dizziness.
    Imatinib: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Indinavir: (Moderate) Concomitant use of hydrocodone with indinavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of indinavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If indinavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Indinavir is a strong inhibitor of CYP3A4.
    Isavuconazonium: (Moderate) Concomitant use of hydrocodone with isavuconazonium may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of isavuconazonium could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If isavuconazonium is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Isavuconazonium is a moderate inhibitor of CYP3A4.
    Isocarboxazid: (Major) Hydrocodone is not recommended for use in patients who have received MAOIs within 14 days. Certain products are contraindicated due to the risk: benefit ratio (e.g., hydrocodone-containing cough syrups). Consider if an alternative to the hydrocodone-containing product is available and appropriate. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Also, potentiation of the effects of the MAOI have been reported, which may increase the risk for adverse events. If combination therapy is necessary, advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Isoflurane: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Isoniazid, INH: (Moderate) Concomitant use of hydrocodone with isoniazid may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of isoniazid could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If isoniazid is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. isoniazid is a weak inhibitor of CYP3A4.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Concomitant use of hydrocodone with isoniazid may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of isoniazid could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If isoniazid is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. isoniazid is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with rifampin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifampin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer.
    Isoniazid, INH; Rifampin: (Moderate) Concomitant use of hydrocodone with isoniazid may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of isoniazid could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If isoniazid is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. isoniazid is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with rifampin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If rifampin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer.
    Itraconazole: (Moderate) Concomitant use of hydrocodone with itraconazole may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of itraconazole could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If itraconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Itraconazole is a strong inhibitor of CYP3A4.
    Ivacaftor: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4.
    Ketamine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include general anesthetics.
    Ketoconazole: (Moderate) Concomitant use of hydrocodone with ketoconazole may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ketoconazole could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ketoconazole is a strong inhibitor of CYP3A4.
    Lactobacillus: (Moderate) Concurrent use of antidiarrheals and opiate agonists, can lead to severe constipation and possibly additive CNS depression. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Lactulose: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as lactulose, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Lapatinib: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Larotrectinib: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Lesinurad: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with lesinurad is necessary; consider increasing the dose of hydrocodone as needed. If lesinurad is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lesinurad is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Lesinurad; Allopurinol: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with lesinurad is necessary; consider increasing the dose of hydrocodone as needed. If lesinurad is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lesinurad is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Letermovir: (Moderate) Concomitant use of hydrocodone with letermovir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of letermovir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If letermovir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
    Levobupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering serotonin norepinephrine reuptake inhibitors (SNRIs), such as levomilnacipran, with other drugs that have serotonergic properties such as hydrocodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Hydrocodone and levomilnacipran should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Levorphanol: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lincosamides: (Moderate) Lincosamides, which have been shown to exhibit neuromuscular blocking action, can enhance the effects of opiate agonists if used concomitantly, enhancing respiratory depressant effects. They should be used together with caution and the patient carefully monitored.
    Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and hydrocodone. Lofexidine can potentiate the effects of CNS depressants.
    Loperamide: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Loperamide; Simethicone: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Lopinavir; Ritonavir: (Moderate) Concomitant use of hydrocodone with lopinavir; ritonavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lopinavir; ritonavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lopinavir; ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lopinavir; ritonavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with ritonavir may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ritonavir could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Ritonavir is a strong inhibitor of CYP3A4 and also inhibits CYP2D6.
    Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
    Lorlatinib: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with lorlatinib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If lorlatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
    Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as opiate agonists. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Lumacaftor; Ivacaftor: (Moderate) Concomitant use of hydrocodone with ivacaftor may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of ivacaftor could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If ivacaftor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Ivacaftor is a weak inhibitor of CYP3A4. (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Lumacaftor; Ivacaftor: (Moderate) Concomitant use of hydrocodone with lumacaftor; ivacaftor can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If lumacaftor; ivacaftor is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as opiate agonists.
    Magnesium Citrate: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as magnesium citrate, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Magnesium Hydroxide: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as magnesium hydroxide, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Minor) Concurrent use of hydrocodone with strong laxatives that rapidly increase gastrointestinal motility, such as magnesium sulfate; potassium sulfate; sodium sulfate, may decrease hydrocodone absorption. Closely monitor patients for changing analgesic requirements or adverse events.
    Maprotiline: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Meclizine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as chlorpheniramine or diphenhydramine, may result in a reduction in the analgesic effect of hydrocodone.
    Mepenzolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Meperidine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Meperidine; Promethazine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Mephobarbital: (Major) Concomitant use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of hydrocodone with barbiturates may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Mepivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mepivacaine; Levonordefrin: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meprobamate: (Moderate) Concomitant use of hydrocodone with meprobamate may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include anxiolytics, sedatives, and hypnotics.
    Mesoridazine: (Moderate) Concomitant use of hydrocodone with other CNS depressants, such as phenothiazines, may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20% to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen is initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tablets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opioid cough medications in patients taking skeletal muscle relaxants.
    Methadone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of hydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methocarbamol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If acetaminophen; hydrocodone or hydrocodone; ibuprofen are initiated in a patient taking a skeletal muscle relaxant, reduced initial doses are recommended. If a decision is made to start treatment with hydrocodone extended-release tabIets or capsules, initiate hydrocodone at 20% to 30% of the usual dosage. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response.