CONTRAINDICATIONS / PRECAUTIONS
General Information
NOTE: This monograph discusses the contraindications/precautions of acetaminophen; hydrocodone combination products. Clinicians may wish to consult the individual monographs for more information about each agent.
Acetaminophen hypersensitivity, opiate agonist hypersensitivity
Acetaminophen; hydrocodone is contraindicated in patients with acetaminophen hypersensitivity. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible. Although true opiate agonist hypersensitivity is rare, the use of acetaminophen; hydrocodone is contraindicated in patients with hydrocodone hypersensitivity.
Acute abdomen, biliary tract disease, constipation, GI disease, GI obstruction, ileus, inflammatory bowel disease, pancreatitis, ulcerative colitis
Hydrocodone is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. Due to the effects of opioid agonists on the gastrointestinal tract, 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. Post-operative patients should be monitored for decreased bowel motility. Opioid agonists may obscure the diagnosis or clinical course in patients with acute abdomen. As with other opioid agonists, hydrocodone may cause spasm of the sphincter of Oddi. Hydrocodone should be used with caution in patients with biliary tract disease, including acute pancreatitis.
Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, cor pulmonale, hypoxemia, respiratory depression, respiratory insufficiency, sleep apnea
Acetaminophen; hydrocodone is contraindicated in persons with significant respiratory depression and those with acute or severe asthma in an unmonitored setting or in the absence of resuscitative equipment. Avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in persons for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective dosages and minimum treatment durations needed. Monitor closely for signs or symptoms of respiratory depression and sedation.[61143] Persons with chronic obstructive pulmonary disease (COPD), cor pulmonale, respiratory insufficiency, hypoxemia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive even at recommended doses. Persons with advanced age, cachexia, or debilitation are also at an increased risk for opioid-induced respiratory depression. Monitor such persons closely, particularly when initiating and titrating the opioid; consider the use of non-opioid analgesics. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in persons with CSA. Respiratory depression, if left untreated, may cause respiratory arrest and death. Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Careful monitoring is required, particularly when CYP450 3A4 inhibitors or inducers are used concomitantly; concurrent use of a CYP3A4 inhibitor or discontinuation of a concurrently used CYP3A4 inducer may increase plasma hydrocodone concentrations and potentiate the risk of fatal respiratory depression. Management of respiratory depression may include observation, necessary supportive measures, and opioid antagonist use when indicated.
Abrupt discontinuation
Avoid abrupt discontinuation of hydrocodone in a physically-dependent patient. When a patient who has been taking opioids regularly and may be physically dependent no longer requires therapy with acetaminophen; hydrocodone, taper the dose gradually while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, 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. Consider tapering to reduced opioid dosage, or tapering and discontinuing long-term opioid therapy, when pain improves; the patient requests dosage reduction or discontinuation; pain and function are not meaningfully improved; the patient is receiving higher opioid doses without evidence of benefit from the higher dose; the patient has current evidence of opioid misuse; the patient experiences side effects that diminish quality of life or impair function; the patient experiences an overdose or other serious event (e.g., hospitalization, injury) or has warning signs for an impending event such as confusion, sedation, or slurred speech; the patient is receiving medications (e.g., benzodiazepines) or has medical conditions (e.g., lung disease, sleep apnea, liver disease, kidney disease, fall risk, advanced age) that increase risk for adverse outcomes; or the patient has been treated with opioids for a prolonged period and current benefit-harm balance is unclear. If the patient has a serious mental illness, is at high suicide risk, or has suicidal ideation, offer or arrange for consultation with a behavioral health provider before initiating a taper. In patients with opioid use disorder, offer or arrange for medication-assisted treatment. Individualize opioid tapering schedules. The longer the duration of previous opioid therapy, the longer the taper may take. Common tapers involve dose reduction of 5% to 20% every 4 weeks; a faster taper may be appropriate for some patients. Significant opioid withdrawal symptoms may indicate the need to pause or slow the taper. Opioids may be stopped, if appropriate, when taken less often than once daily. Advise patients that there is an increased risk for overdose on abrupt return to a previously prescribed higher dose; provide opioid overdose education, and consider offering naloxone. Monitor patients closely for anxiety, depression, suicidal ideation, and opioid use disorder, and offer support and referral as needed.
Accidental exposure, alcoholism, depression, ethanol intoxication, hepatic disease, hepatitis, hepatotoxicity, hypovolemia, malnutrition, opioid overdose, opioid use disorder, potential for overdose or poisoning, requires an experienced clinician, substance abuse
Acetaminophen has the potential for overdose or poisoning causing hepatotoxicity and acute liver failure, at times resulting in liver transplantation and death. Most cases of liver injury are associated with the use of acetaminophen at doses exceeding 4 g/day and often involve the use of more than 1 acetaminophen-containing product. Use caution during the measurement of oral liquid dosage forms to minimize the risk of dosing errors that can result in accidental overdose. Advise patients receiving acetaminophen to carefully read OTC and prescription labels, to avoid excessive and/or duplicate medications, and to seek medical help immediately if more than 4 g/day of acetaminophen is ingested, even if they feel well. It is important to note that the risk of acetaminophen-induced hepatotoxicity is increased in patients with pre-existing hepatic disease (e.g., hepatitis), those who ingest alcohol (e.g., ethanol intoxication, alcoholism), those with chronic malnutrition, and those with severe hypovolemia. In patients with chronic hepatic disease, acetaminophen can be used safely in recommended doses and is often preferred to nonsteroidal anti-inflammatory drugs (NSAIDs) due to the absence of platelet impairment, gastrointestinal toxicity, and nephrotoxicity. Though the half-life of acetaminophen may be prolonged, repeated dosing does not result in drug or metabolite accumulation. In addition, cytochrome P450 activity is not increased and glutathione stores are not depleted in hepatically impaired patients taking therapeutic doses, therefore toxic metabolite formation and accumulation is not altered. Although it is always prudent to use the smallest dose of acetaminophen for the shortest duration necessary, courses less than 2 weeks in length have been administered safely to adult patients with stable chronic liver disease. Additionally, patients with hepatic impairment may have higher plasma hydrocodone concentrations compared to those with normal hepatic function. Use a low initial dose of acetaminophen; hydrocodone in patients with hepatic impairment, and monitor for sedation and respiratory depression. Opioid use requires an experienced clinician who is knowledgeable about the use of opioids and how to mitigate the associated risks. Opioids expose users to the risks of addiction, abuse, and misuse, which can occur at any dosage or duration. Although the risk of addiction in any individual is unknown, it can occur in persons appropriately prescribed an opioid. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each individual's risk for opioid addiction, abuse, or misuse before prescribing an opioid, and monitor for the development of these behaviors or conditions. Risks are increased in persons with a personal or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression). The potential for these risks should not prevent the proper management of pain in any given individual. Persons at increased risk may be prescribed opioids but use in such persons necessitates intensive counseling about the risks and proper use of the opioid along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse and addiction are separate and distinct from physical dependence and tolerance; persons with addiction may not exhibit tolerance and symptoms of physical dependence. Opioids are sought by drug abusers and persons with addiction disorders and are subject to criminal diversion. Abuse of opioids has the potential for overdose or poisoning and death. Consider these risks when prescribing or dispensing opioids. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Dosing errors may result from confusion between mg and mL when prescribing, dispensing, and administering acetaminophen; hydrocodone oral solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients on how to measure the dose and to use a calibrated oral dosing device. Keep opioids out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets as accidental exposure or improper use may cause respiratory failure and a fatal overdose. Accidental exposure of even a single dose of an opioid, especially by younger persons, can result in a fatal overdose. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of an opioid for persons in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Do not use immediate-release opioids for an extended period unless the pain remains severe enough to require an opioid and for which alternative treatment options continue to be inadequate. Many acute pain conditions (e.g., pain occurring with surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid. Clinical guidelines on opioid prescribing for some acute pain conditions are available. Discuss the availability of naloxone with all patients and consider prescribing it in persons who are at increased risk of opioid overdose, such as those who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental exposure or opioid overdose.
Brain tumor, CNS depression, coma, head trauma, increased intracranial pressure, intracranial mass
Avoid acetaminophen; hydrocodone use in persons with CNS depression, impaired consciousness, or coma; opioids may obscure the clinical course in a person with a head trauma injury. Monitor persons who may be susceptible to the intracranial effect of carbon dioxide retention (e.g., those with evidence of increased intracranial pressure, brain tumor, or intracranial mass) for signs of sedation and respiratory depression, particularly when initiating acetaminophen; hydrocodone therapy. Hydrocodone may reduce respiratory drive and resultant carbon dioxide retention can further increase intracranial pressure.
Angina, cardiac arrhythmias, cardiac disease, dehydration, hypotension, orthostatic hypotension, shock
Opioid agonists, such as hydrocodone, produce cholinergic side effects (by stimulating medullary vagal nuclei) causing bradycardia and vasovagal syncope, and induce the release of histamine. In patients who are unable to maintain blood pressure due to hypovolemia or dehydration, or in those who concurrently receive other agents that compromise vasomotor tone (e.g., phenothiazines or general anesthetics), opioid agonists may induce peripheral vasodilatation and severe hypotension. These effects can cause problems in patients with cardiac disease (e.g., angina, heart failure). Hydrocodone should be used with caution in patients with cardiac arrhythmias or orthostatic hypotension and should not be used in patients with circulatory shock. Monitor patients for hypotension following hydrocodone initiation and dose titrations.
Bladder obstruction, oliguria, prostatic hypertrophy, renal impairment, urethral stricture, urinary retention
Acetaminophen; hydrocodone should be used cautiously in patients with renal impairment or renal failure; dosage adjustments may be required. Hydrocodone can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with prostatic hypertrophy, urethral stricture, bladder obstruction, or pelvic tumors. In addition, hydrocodone may accumulate in these patients leading to a prolonged duration of action and potential increase in side effects. Chronic acetaminophen administration should be avoided in patients with underlying renal disease; however it may be used for episodic pain.
Geriatric
Use hydrocodone with caution in geriatric or debilitated patients. Geriatric or debilitated patients are more susceptible to adverse reactions, especially sedation and respiratory depression, probably as a result of the altered distribution of the drug or decreased elimination. Initial doses may need to be reduced, and doses should be carefully titrated, taking into account analgesic effects, adverse reactions, and concomitant conditions and drugs that may increase CNS depression and depress respiration.[45955] 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 patient populations, except in the setting of severe acute pain, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk. In patients receiving palliative care or hospice, the balance of benefits and harms of medication management may differ from those of the general population of older adults.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). OBRA cautions that opioids may cause constipation, nausea, vomiting, sedation, lethargy, weakness, confusion, dysphoria, physical and psychological dependency, hallucinations, and unintended respiratory depression, especially in individuals with compromised pulmonary function. These adverse effects can lead to other consequences such as falls. The initiation of longer-acting opioids is not recommended unless shorter-acting opioids have been unsuccessful, or titration of shorter-acting doses has established a clear daily dose of opioid analgesic that can be provided by using a long-acting form.[60742]
G6PD deficiency
Patients with G6PD deficiency who overdose with acetaminophen may be at increased risk for drug-induced hemolysis. Practitioners should be aware of this potential complication and monitor at-risk patients for signs and symptoms of hemolysis. Conflicting data exists on whether therapeutic doses of acetaminophen can cause hemolysis in G6PD deficient patients. However, a direct cause and effect relationship has not been well established and therefore, therapeutic doses are generally considered safe in this population.
Bone marrow suppression, immunosuppression, infection, neutropenia
Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen in patients with bone marrow suppression, especially neutropenia, or immunosuppression.
Driving or operating machinery
Any patient receiving acetaminophen; hydrocodone should be warned about the possibility of sedation and to use caution when driving or operating machinery.
Seizure disorder, seizures
Seizures can be precipitated by opioid agonists in patients with a preexisting seizure disorder. The incidence of these effects during hydrocodone therapy is not known, but appears to be rare at normal doses. Monitor patients with a history of seizure disorders for worsened seizure control during therapy.
Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy
Use acetaminophen; hydrocodone during pregnancy only if the potential benefit clearly justifies the potential risk to the fetus. There are no adequate and well-controlled studies of acetaminophen; hydrocodone in pregnant women. Published epidemiological studies have not reported a clear association with acetaminophen use during pregnancy and birth defects, miscarriage, or adverse maternal or fetal outcomes. Large observational studies of newborns exposed to oral acetaminophen during the first trimester have not shown an increased risk for congenital malformations or major birth defects; however, these studies cannot definitely establish the absence of risk because of methodological limitations. Acetaminophen does cross the placenta and should be used during pregnancy only if the benefits to the mother outweigh the potential risks to the fetus or infant. No overall increase in fetal mortality, determined by pregnancy outcomes of mothers that overdosed on various amounts of oral acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 infants exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. None of the infants with malformations were exposed during the first trimester, but all of the spontaneous abortions were subsequent to first trimester exposure. 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. Acetaminophen; hydrocodone is not recommended for use during and immediately before labor when other analgesic techniques are more appropriate. Opioids can prolong labor and obstetric delivery by temporarily reducing the strength, duration, and frequency of uterine contractions. This effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. An opioid antagonist (e.g., naloxone) should be available for reversal of opioid-induced respiratory depression in the neonate. Further, prolonged maternal use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Monitor the exposed neonate for withdrawal symptoms, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight, and manage accordingly. 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. Guidelines recommend early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Obtain a thorough history of substance use and review the Prescription Drug Monitoring Program to determine if patients have received prior prescriptions for opioids or other high-risk drugs such as benzodiazepines. Discuss the risks and benefits of opioid use during pregnancy, including the risk of becoming physiologically dependent on opioids, the possibility for NOWS, and how long-term opioid use may affect care during a future pregnancy.[64838] [64909] In women undergoing uncomplicated normal spontaneous vaginal birth, consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, use in combination with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. Use immediate-release opioids instead of extended-release or long-acting opioids; order the lowest effective dosage and prescribe no greater quantity of opioids than needed for the expected duration of such pain severe enough to require opioids.[64909] For women using opioids for chronic pain, consider strategies to avoid or minimize the use of opioids, including alternative pain therapies (i.e., nonpharmacologic) and nonopioid pharmacologic treatments. Opioid agonist pharmacotherapy (e.g., methadone or buprenorphine) is preferable to medically supervised withdrawal in pregnant women with opioid use disorder.[64838]
Breast-feeding
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for acetaminophen; hydrocodone and any potential adverse effects on the breast-fed infant from the drugs or the underlying maternal condition. Hydrocodone is distributed into breast milk at varying degrees depending upon the dose. Acetaminophen also crosses into breast milk with a concentration ranging from 0.1% to 1.85% of the maternal dose. A pharmacokinetic study in 30 women receiving acetaminophen; 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 older infants. 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. As with all opioid-containing products, if acetaminophen; hydrocodone is used by a breast-feeding mother, the infant should be monitored for sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Previous American Academy of Pediatrics (AAP) recommendations considered acetaminophen as usually compatible with breast-feeding. Other alternative analgesics considered to be usually compatible with breast-feeding by the AAP include ibuprofen and morphine; the use of hydrocodone in breast-feeding women was not evaluated by the AAP.
Infertility, reproductive risk
Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression) and pose a reproductive risk. Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. It is not known whether the effects on fertility are reversible. Monitor patients for symptoms of opioid-induced endocrinopathy. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.
DRUG INTERACTIONS
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
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; Aspirin; Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
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; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine 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.
Acetaminophen; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
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: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
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: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
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; Pamabrom; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine 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.
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.
Acrivastine; Pseudoephedrine: (Major) Avoid coadministration of opioid agonists with acrivastine due to the risk of additive CNS depression.
Adagrasib: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A and CYP2D6 substrate, and coadministration with dual CYP3A and CYP2D6 inhibitors like adagrasib can significantly increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when added to a stable dose of hydrocodone. If adagrasib 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.
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; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
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.
Amiloride: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for decreased diuretic efficacy and additive orthostatic hypotension when amiloride is administered with hydrocodone. Adjustments to diuretic therapy may be needed in some patients. The efficacy of diuretics may be reduced due to opioid-induced release of antidiuretic hormone. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Amiodarone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amiodarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like amiodarone 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If amiodarone 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.
Amlodipine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine 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 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine 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.
Amlodipine; Atorvastatin: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine 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 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine 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.
Amlodipine; Benazepril: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine 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 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine 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.
Amlodipine; Celecoxib: (Moderate) Concomitant use of hydrocodone with celecoxib 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 celecoxib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If celecoxib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Celecoxib is an inhibitor of CYP2D6. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine 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 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine 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.
Amlodipine; Olmesartan: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine 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 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine 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.
Amlodipine; Valsartan: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine 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 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine 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.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine 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 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine 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. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Amobarbital: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Amoxapine: (Major) Concomitant use of opioid agonists with amoxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with amoxapine 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. Educate patients about the risks and symptoms of excessive CNS depression.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin 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 clarithromycin 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin 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.
Amphetamine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Amphetamine; Dextroamphetamine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Amphetamines: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Antacids: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
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: (Major) Concomitant use of opioid agonists with apomorphine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking apomorphine. Limit the use of opioid pain medications with entacapone 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. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like apomorphine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of oral, multi-day regimens of aprepitant 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 aprepitant 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If aprepitant 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. (Minor) Use caution if acetaminophen and aprepitant are used concurrently and monitor for an increase in acetaminophen-related adverse effects for several days after administration of a multi-day aprepitant regimen. Acetaminophen is a minor (10 to 15%) substrate of CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of acetaminophen. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole 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. Educate patients about the risks and symptoms of excessive CNS depression.
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) Coadministration of articaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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.
Asciminib: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of asciminib is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like asciminib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If asciminib 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.
Asenapine: (Moderate) Concomitant use of opioid agonists with asenapine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking asenapine. Limit the use of opioid pain medications with asenapine 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. Educate patients about the risks and symptoms of excessive CNS depression.
Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (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. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Concomitant use of opioid agonists with orphenadrine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with orphenadrine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking orphenadrine.
Aspirin, ASA; Carisoprodol: (Major) Concomitant use of opioid agonists with carisoprodol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking carisoprodol.
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 opioid agonists with carisoprodol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking carisoprodol.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir 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 atazanavir 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If atazanavir 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.
Atazanavir; Cobicistat: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir 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 atazanavir 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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.
Atenolol; Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Atropine: (Major) Reserve concomitant use of hydrocodone and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Major) Reserve concomitant use of hydrocodone and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Atropine; Difenoxin: (Major) Reserve concomitant use of hydrocodone and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) 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.
Atropine; Edrophonium: (Major) Reserve concomitant use of hydrocodone and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Avacopan: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If avacopan 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.
Azelastine: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking azelastine. Limit the use of opioid pain medications with azelastine 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. Educate patients about the risks and symptoms of excessive CNS depression.
Azelastine; Fluticasone: (Major) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking azelastine. Limit the use of opioid pain medications with azelastine 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. Educate patients about the risks and symptoms of excessive CNS depression.
Azilsartan; Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Baclofen: (Major) Concomitant use of opioid agonists with baclofen may cause excessive sedation and somnolence. Limit the use of opioid pain medications with baclofen to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking baclofen.
Barbiturates: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
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 for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and belladonna use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Belumosudil: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of belumosudil is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like belumosudil 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If belumosudil 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.
Belzutifan: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with belzutifan is necessary; consider increasing the dose of hydrocodone as needed. If belzutifan is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A substrate and belzutifan is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Bendroflumethiazide; Nadolol: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Benzhydrocodone; Acetaminophen: (Major) Benzhydrodocone is a prodrug for hydrocodone. Use caution to avoid duplicate therapy. Concomitant use of opioid agonists with benzhydrocodone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of benzhydrocodone with opioid agonists 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 benzhydrocodone is initiated in a patient taking morphine, reduce initial dosage and titrate to clinical response. If morphine is prescribed in a patient taking benzhydrocodone, use a lower initial dose of morphine 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 other opioid agonists. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and morphine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. 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.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of hydrocodone in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and hyoscyamine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Benzphetamine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Benztropine: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and benztropine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Berotralstat: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like berotralstat 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If berotralstat 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.
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.
Bicalutamide: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide 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 bicalutamide 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If bicalutamide 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.
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) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
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.
Brexanolone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Brexpiprazole: (Major) Concomitant use of opioid agonists with brexpiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking brexpiprazole. Limit the use of opioid pain medications with brexpiprazole 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. Educate patients about the risks and symptoms of excessive CNS depression.
Brigatinib: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with brigatinib is necessary; consider increasing the dose of hydrocodone as needed. If brigatinib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and brigatinib 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.
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 opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine 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.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and glycopyrrolate use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Bumetanide: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and hydrocodone; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms.
Buprenorphine; Naloxone: (Major) Avoid concomitant use of hydrocodone and a mixed opioid agonist/antagonist, such as buprenorphine, due to risk for reduced analgesic effect of hydrocodone and/or precipitation of withdrawal symptoms.
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.
Busulfan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Butabarbital: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of hydrocodone 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. It is recommended to avoid this combination when hydrocodone is being used for cough. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concomitant use of hydrocodone with a barbiturate can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal. Discontinuation of a barbiturate may increase the risk of opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates induce CYP3A4; hydrocodone is a CYP3A4 substrate. (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. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
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, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Cannabidiol: (Moderate) Concomitant use of opioid agonists with cannabidiol may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking cannabidiol. Limit the use of opioid pain medications 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. Educate patients about the risks and symptoms of excessive CNS depression.
Capsaicin; Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause respiratory depression, profound sedation, and death. Limit the use of opioid pain medication with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking metaxalone. Educate patients about the risks and symptoms of respiratory depression and sedation. Consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use of metaxalone and opioid agonists increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
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. (Minor) Carbamazepine may potentially accelerate the hepatic metabolism of acetaminophen. In addition, due to enzyme induction, carbamazepine may increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Clinicians should be alert to decreased effect of acetaminophen. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
Carbinoxamine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine 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.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine 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.
Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine 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.
Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine 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.
Cariprazine: (Moderate) Concomitant use of opioid agonists like hydrocodone with cariprazine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cariprazine 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. Avoid prescribing opioid cough medication in patients taking cariprazine.
Carisoprodol: (Major) Concomitant use of opioid agonists with carisoprodol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking carisoprodol.
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.
Celecoxib: (Moderate) Concomitant use of hydrocodone with celecoxib 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 celecoxib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If celecoxib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Celecoxib is an inhibitor of CYP2D6.
Celecoxib; Tramadol: (Major) Concomitant use of hydrocodone with tramadol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of hydrocodone with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Additionally, monitor patients for seizures and/or the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Concomitant use of hydrocodone with celecoxib 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 celecoxib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If celecoxib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Celecoxib is an inhibitor of CYP2D6.
Cenobamate: (Moderate) Concomitant use of hydrocodone with cenobamate may cause excessive sedation and somnolence. Limit the use of hydrocodone with cenobamate 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. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing hydrocodone cough medication in patients taking cenobamate. Additionally, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with cenobamate is necessary; consider increasing the dose of hydrocodone as needed. If cenobamate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone concentrations.
Ceritinib: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ceritinib 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 ceritinib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ceritinib 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.
Cetirizine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cetirizine; Pseudoephedrine: (Major) Reserve concomitant use of opioids and cetirizine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Charcoal: (Minor) Activated charcoal binds many drugs within the gut. Administering charcoal dietary supplements at the same time as a routine acetaminophen dosage would be expected to interfere with the analgesic and antipyretic efficacy of acetaminophen. Charcoal is mostly used in the setting of acetaminophen overdose; however, patients should never try to treat an acetaminophen overdose with charcoal dietary supplements. Advise patients to get immediate medical attention for an acetaminophen overdose.
Chlophedianol; Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine 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.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine 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.
Chloramphenicol: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of chloramphenicol 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 chloramphenicol 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If chloramphenicol 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.
Chlorcyclizine: (Moderate) Concomitant use of opioid agonists with chlorcyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorcyclizine 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.
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; Amitriptyline: (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.
Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (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) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
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 opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
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 opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine 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.
Chlorpromazine: (Major) Concomitant use of opioid agonists with chlorpromazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking chlorpromazine. Limit the use of opioid pain medications with chlorpromazine 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. Educate patients about the risks and symptoms of excessive CNS depression.
Chlorthalidone: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Chlorthalidone; Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine 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. (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Chlorzoxazone: (Major) Concomitant use of opioid agonists with chlorzoxazone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chlorzoxazone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking chlorzoxazone.
Cholestyramine: (Moderate) Cholestyramine has been shown to decrease the absorption of acetaminophen by roughly 60%. Experts have recommended that cholestyramine not be given within 1 hour of acetaminophen if analgesic or antipyretic effect is to be achieved.
Choline Salicylate; Magnesium Salicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
Cimetidine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine 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.
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 moderate inhibitor of CYP2D6.
Ciprofloxacin: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ciprofloxacin 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 ciprofloxacin 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ciprofloxacin 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.
Citalopram: (Moderate) Serotonin syndrome can occur during concomitant use of opiate agonists like hydrocodone with serotonergic drugs, such as citalopram. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Clarithromycin: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin 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 clarithromycin 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If clarithromycin 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.
Clemastine: (Moderate) Concomitant use of opioid agonists with clemastine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clemastine 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.
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: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine 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.
Clopidogrel: (Moderate) Coadministration of opioid agonists, such as hydrocodone, 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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.
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; 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.
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. (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS 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. (Major) Concomitant use of opioid agonists with promethazine may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking promethazine. Limit the use of opioid pain medications with promethazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce the opioid dose by one-quarter to one-half; use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
COMT inhibitors: (Major) Concomitant use of opioid agonists with COMT inhibitors may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking COMT inhibitors. Limit the use of opioid pain medications with COMT inhibitors 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. Educate patients about the risks and symptoms of excessive CNS depression. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
Conivaptan: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan 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.
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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. 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 opioid agonists with cyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cyclizine 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. Educate patients about the risks and symptoms of excessive CNS depression.
Cyclobenzaprine: (Major) Concomitant use of hydrocodone with cyclobenzaprine may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome and anticholinergic effects. Limit the use of opioid pain medications with cyclobenzaprine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking cyclobenzaprine. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Cyclosporine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cyclosporine 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 cyclosporine 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If cyclosporine 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.
Cyproheptadine: (Moderate) Concomitant use of opioid agonists with cyproheptadine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cyproheptadine 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.
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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dalfopristin; quinupristin is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like dalfopristin; quinupristin 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If dalfopristin; quinupristin 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.
Danazol: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of danazol 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 danazol 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If danazol 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.
Dantrolene: (Major) Concomitant use of opioid agonists with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid agonists with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Avoid prescribing opioid cough medication in patients taking dantrolene.
Dapsone: (Moderate) Coadministration of dapsone with acetaminophen may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Daridorexant: (Major) Concomitant use of opiate agonists with daridorexant may cause excessive sedation and somnolence. Limit the use of opiates with daridorexant 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. Educate patients about the risks and symptoms of excessive CNS depression. Avoid prescribing cough medicines that contain opiates in patients taking daridorexant.
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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir 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 darunavir 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir 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.
Darunavir; Cobicistat: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir 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 darunavir 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir 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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir 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 darunavir 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir 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.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir 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 ritonavir 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir 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.
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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of delavirdine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like delavirdine 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If delavirdine 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.
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.
Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
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.
Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine 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.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine 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.
Dexchlorpheniramine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine 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.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine 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.
Dexmedetomidine: (Moderate) Concomitant use of opioid agonists with dexmedetomidine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with dexmedetomidine 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.
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.
Dextroamphetamine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Dextromethorphan; 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.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
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 for signs of urinary retention or reduced gastric motility during concomitant hydrocodone and dicyclomine use. Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Difelikefalin: (Major) Avoid concomitant use of opioids and other CNS depressants, such as difelikefalin. Concomitant use can increase the risk of respiratory depression, hypotension, profound sedation, and death. If alternate treatment options are inadequate and coadministration is necessary, limit dosages and durations to the minimum required, monitor patients closely for respiratory depression and sedation, and consider prescribing naloxone for the emergency treatment of opioid overdose.
Diflunisal: (Moderate) Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.
Diltiazem: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem 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 diltiazem 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If diltiazem 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.
Dimenhydrinate: (Moderate) Concomitant use of opioid agonists with dimenhydrinate may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dimenhydrinate 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.
Diphenhydramine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Ibuprofen: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Naproxen: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenhydramine; Phenylephrine: (Major) Reserve concomitant use of opioids and diphenhydramine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Diphenoxylate; Atropine: (Major) Reserve concomitant use of hydrocodone and atropine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) 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.
Dolasetron: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-receptor antagonists. The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists, mostly when used in combination with other serotonergic medications. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Doxylamine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Doxylamine; Pyridoxine: (Major) Reserve concomitant use of opioids and doxylamine for patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose and monitor for signs of urinary retention or reduced gastric motility. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus.
Dronabinol: (Moderate) Concomitant use of opioid agonists with dronabinol may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dronabinol 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.
Dronedarone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of dronedarone is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like dronedarone 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If dronedarone 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.
Droperidol: (Major) Concomitant use of opioid agonists with droperidol may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking droperidol. Limit the use of opioid pain medications with droperidol 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. Educate patients about the risks and symptoms of excessive CNS depression.
Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Duloxetine: (Moderate) 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.
Duvelisib: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of duvelisib 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 duvelisib 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If duvelisib 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.
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. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efavirenz; Emtricitabine; 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. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
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. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
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.
Elagolix; Estradiol; Norethindrone acetate: (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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of grazoprevir 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 grazoprevir 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If grazoprevir 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.
Eletriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering hydrocodone with serotonin-recptor agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ivacaftor is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ivacaftor 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ivacaftor 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.
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. Acetaminophen is a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of acetaminophen are possible. Monitor patients for adverse reactions if these drugs are coadministered.
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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
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) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a thiazide diuretic and hydrocodone; increase the dosage of the thiazide diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Opioids may also potentiate orthostatic hypotension when given concomitantly with a thiazide diuretic.
Erythromycin: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of erythromycin 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 erythromycin 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. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If erythromycin 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.
Escitalopram: (Moderate) 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. 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.
Esketamine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine 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. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
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: (Major) Concomitant use of opioid agonists with eszopiclone may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Avoid prescribing opioid cough medications in patients taking eszopiclone. Limit the use of opioid pain medications with eszopiclone 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. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
Ethacrynic Acid: (Moderate) Monitor for signs of diminished diuresis and/or effects on blood pressure during coadministration of a loop diuretic and hydrocodone; increase the dosage of the loop diuretic as needed. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking opioids. Alcohol consumption may result in additive CNS depression and may increase the risk for opioid overdose. Alcohol may also increase opioid drug exposure and the risk for fatal overdose by disrupting extended- or delayed-release opioid formulations. Consider the patient's use of alcohol when prescribing opioid medications. If the patient is unlikely to be compliant with avoiding alcohol, consider prescribing naloxone especially if additional risk factors for opioid overdose are present. (Major) The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume alcohol. Patients who drink more than 3 alcohol-containing drinks a day and take acetaminophen are at increased risk of developing hepatotoxicity. Acute or chronic alcohol use increases acetaminophen-induced hepatotoxicity by inducing CYP2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume alcohol regularly.
Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Etomidate: (Major) Concomitant use of hydrocodone with a general anesthetic may cause respiratory depression, hypotension, profound sedation, and death. Avoid prescribing opioid cough medications in patients receiving a general anesthetic. Limit the use of opioid pain medications with a general anesthetic to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of everolimus is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If everolimus 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.
Exenatide: (Minor) Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
Fedratinib: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of fedratinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like fedratinib 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. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If fedratinib 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.
Fenfluramine: (Moderate) Concomitant use of opioid agonists with fenfluramine may cause excessive sedation and somnolence. Limit the use of opioid agonists with fenfluramine to only patients for whom alternative treatment options are inadequate. If concurren