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    Opioid Agonists and Other Drug Combinations

    BOXED WARNING

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, pulmonary disease, respiratory depression

    As with other opioid agonists, products containing codeine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Acetaminophen; codeine should be used cautiously in patients with asthma. In addition, codeine should be avoided in patients with severe pulmonary disease such as acute or severe bronchial asthma, chronic obstructive pulmonary disease (COPD), or upper airway obstruction, patients with decreased respiratory reserve or in patients with significant respiratory depression due to potential additive affects.

    Alcoholism, ethanol intoxication, hepatic disease, hepatitis, potential for overdose or poisoning

    Acetaminophen has the potential for overdose or poisoning causing acute liver failure, at times resulting in liver transplant and death. Most cases of liver injury are associated with the use of acetaminophen at doses exceeding 4 grams per day and often involve the use of more than one acetaminophen-containing product. 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 grams of acetaminophen is ingested in 1 day, 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 dehydration. 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. Further, patients with severe hepatic disease may experience increased toxicity and reduced analgesic effects from codeine. Codeine is primarily metabolized by the liver, and conversion to morphine is necessary for analgesic effects. Codeine may not be a good analgesic choice for patients with severe hepatic impairment. In acute situations, lower doses and/or less frequent dosing intervals may be needed. Carefully monitor patients for codeine efficacy and toxicity.

    Adenoidectomy, children, infants, neonates, obesity, respiratory infection, sleep apnea, tonsillectomy

    Acetaminophen; codeine is contraindicated for the treatment of pain in neonates, infants, and children younger than 12 years. The use of acetaminophen; codeine for postoperative pain management in pediatric patients of all ages after a tonsillectomy and/or adenoidectomy is also contraindicated. The American Academy of Pediatrics (AAP) recommends against the use of codeine in all pediatric patients for any indication. Do not use acetaminophen; codeine in pediatric patients who have obesity or conditions which may increase the risk of serious breathing problems (e.g., obstructive sleep apnea, severe lung disease, asthma, respiratory infection). Codeine metabolism is highly variable and unpredictable, particularly in children younger than 12 years; therapeutic response to recommended doses can range from lack of effect in poor metabolizers to fatality in ultra-rapid metabolizers. Ultra-rapid metabolizers are more likely to convert codeine to morphine quickly, leading to excessive morphine blood concentrations that can result in fatal respiratory depression. Because some children who are normal metabolizers can convert codeine to morphine at rates similar to ultra-metabolizers, this concern extends to all pediatric patients.

    DEA CLASS

    Rx, schedule V, schedule III

    DESCRIPTION

    Acetaminophen is a non-salicylate; codeine is an opiate agonist
    Used for mild to moderate pain; combination produces additive analgesia
    Codeine metabolism is highly variable and unpredictable; use in patients younger than 12 years is contraindicated

    COMMON BRAND NAMES

    Capital and Codeine, Tylenol with Codeine No.3, Tylenol with Codeine No.4

    HOW SUPPLIED

    Acetaminophen, Codeine Phosphate Oral Liq: 5mL, 120-12mg
    Acetaminophen, Codeine Phosphate Oral Sol: 5mL, 120-12mg
    Acetaminophen, Codeine Phosphate/Capital and Codeine Oral Susp: 5mL, 120-12mg
    Acetaminophen, Codeine Phosphate/Tylenol with Codeine No.3/Tylenol with Codeine No.4 Oral Tab: 300-15mg, 300-30mg, 300-60mg

    DOSAGE & INDICATIONS

    For the treatment of mild pain to moderate pain.
    Oral dosage (tablets)
    Adults

    1 to 2 tablets PO every 4 hours as needed. Maximum single dose of codeine is 60 mg/dose. Maximum daily dose: 360 mg of codeine and 4,000 mg of acetaminophen.

    Oral dosage (liquid formulations containing 120 mg of acetaminophen and 12 mg of codeine per 5 mL)
    Adults

    15 mL PO every 4 hours as needed. Max: 360 mg of codeine and 4,000 mg of acetaminophen per 24 hours.

    Adolescents

    0.5 mg/kg/dose of codeine component, up to 15 mL (codeine 36 mg and acetaminophen 360 mg) PO every 4 hours as needed. Max: 360 mg of codeine and 4,000 mg of acetaminophen per 24 hours.

    Children 12 years

    0.5 mg/kg/dose of codeine component, up to 10 mL (codeine 24 mg and acetaminophen 240 mg) PO 3 to 4 times daily as needed. Max: 75 mg/kg/day or 4,000 mg/day of acetaminophen, whichever is less.

    For the treatment of nonproductive cough†.
    Oral dosage
    Adults

    10 to 20 mg codeine PO every 4 to 6 hours as needed. Maximum codeine dose should not exceed 120 mg/24 hours when used as an antitussive and maximum acetaminophen dose is 4 g/day.

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: For combination products containing acetaminophen, total daily intake of acetaminophen from all sources should be considered and may be the dose-limiting consideration for acetaminophen; codeine products.

    Adults

    Acetaminophen 4,000 mg/day PO; codeine 60 mg/dose PO; some clinicians have recommended the following maximum dosages: for pain, codeine 360 mg/day PO; as an antitussive, codeine 120 mg/day PO.

    Geriatric

    Acetaminophen 4,000 mg/day PO; codeine 60 mg/dose PO; some clinicians have recommended the following maximum dosages: for pain, codeine 360 mg/day PO; as an antitussive, codeine 120 mg/day PO.

    Adolescents

    Acetaminophen 4,000 mg/day PO; codeine 60 mg/dose PO and 360 mg/day PO.

    Children

    12 years: Acetaminophen 75 mg/kg/day PO or 4,000 mg/day PO, whichever is less; FDA-approved labeling recommends 0.5 mg/kg/dose of codeine, or 10 mL (24 mg of codeine) per dose up to 4 times daily.
    1 to 11 years: Use is contraindicated.

    Infants

    Use is contraindicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage should be modified depending upon the clinical response and degree of hepatic impairment. No quantitative recommendations are available.

    Renal Impairment

    Dosage should be modified depending upon the clinical response and degree of renal impairment. No quantitative recommendations are available.

    ADMINISTRATION

    Oral Administration

    Administer with a full glass of water. May be taken with food or milk to minimize GI irritation.
    Acetaminophen; codeine should be titrated to the dose required to relieve the patient's pain keeping in mind the maximum daily dose of acetaminophen. Careful titration in opioid-naive patients is required until tolerance develops to some of the side effects (i.e., drowsiness, respiratory depression).

    Oral Solid Formulations

    Strengths of commercially available tablets do not correspond to the doses for antitussive use.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Capital and Codeine:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Cocet:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Cocet Plus:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol with Codeine No.3:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol with Codeine No.4:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the contraindications/precautions of acetaminophen; codeine combination products. Clinicians may wish to consult the individual monographs for more information about each agent.

    Acetaminophen hypersensitivity, opiate agonist hypersensitivity, sulfite hypersensitivity

    Acetaminophen; codeine combinations are contraindicated in patients with known acetaminophen hypersensitivity. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible. Although true opiate agonist hypersensitivity is rare, use of acetaminophen; codeine is contraindicated in patients who have demonstrated a prior codeine hypersensitivity reaction. Such patients should not receive other opioid agonists of the phenanthrene subclass including morphine, oxycodone, and hydromorphone. Use caution in patients with sulfite hypersensitivity, as some acetaminophen; codeine tablets contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible patients. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

    Constipation, diarrhea, GI disease, GI obstruction, ileus, inflammatory bowel disease, ulcerative colitis

    Due to the effects of opiate agonists on the gastrointestinal tract, acetaminophen; codeine should be used cautiously in patients with GI disease including GI obstruction or ileus, ulcerative colitis, or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Use acetaminophen; codeine with caution in patients who have or are suspected of having a paralytic ileus. Patients with acute ulcerative colitis or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Although opiate agonists may worsen systemic symptoms and/or lengthen disease course in cases of diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opiate agonists should not be given until the toxic substance has been eliminated.

    Asthma, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, pulmonary disease, respiratory depression

    As with other opioid agonists, products containing codeine should be avoided in patients with severe pulmonary disease. Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Acetaminophen; codeine should be used cautiously in patients with asthma. In addition, codeine should be avoided in patients with severe pulmonary disease such as acute or severe bronchial asthma, chronic obstructive pulmonary disease (COPD), or upper airway obstruction, patients with decreased respiratory reserve or in patients with significant respiratory depression due to potential additive affects.

    Abrupt discontinuation

    Abrupt discontinuation of prolonged acetaminophen; codeine therapy can result in withdrawal symptoms (see Adverse Reactions). Patients should be gradually tapered off acetaminophen; codeine to avoid a withdrawal reaction. Generally, a 50% decrease every 1—2 days of the daily acetaminophen; codeine dose will prevent withdrawal symptoms in patients who have been receiving large daily doses of codeine.

    Alcoholism, ethanol intoxication, hepatic disease, hepatitis, potential for overdose or poisoning

    Acetaminophen has the potential for overdose or poisoning causing acute liver failure, at times resulting in liver transplant and death. Most cases of liver injury are associated with the use of acetaminophen at doses exceeding 4 grams per day and often involve the use of more than one acetaminophen-containing product. 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 grams of acetaminophen is ingested in 1 day, 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 dehydration. 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. Further, patients with severe hepatic disease may experience increased toxicity and reduced analgesic effects from codeine. Codeine is primarily metabolized by the liver, and conversion to morphine is necessary for analgesic effects. Codeine may not be a good analgesic choice for patients with severe hepatic impairment. In acute situations, lower doses and/or less frequent dosing intervals may be needed. Carefully monitor patients for codeine efficacy and toxicity.

    Substance abuse

    Because codeine is an opiate agonist, acetaminophen; codeine is subject to substance abuse and psychologic dependence (i.e., drug addiction) or criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk for harm. Patients with a previous history of substance abuse may be at increased risk of relapse if treated with acetaminophen; codeine. Abuse and addiction are separate and distinct from physiologic dependence and tolerance. Physicians should be aware that psychologic dependence may not be accompanied by concurrent tolerance and symptoms of physiologic dependence. In addition, abuse of opiate agonists can occur in the absence of true psychologic dependence and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Health care professionals should not let concerns over psychologic dependence deter them from using adequate amounts of opiate agonists in the management of severe pain. Patients should also be counseled regarding misconceptions regarding the use of opiate agonists for pain management. Acetaminophen; codeine is not approved for the management of substance abuse (alcohol or drug dependence). The use of acetaminophen; codeine in patients with alcohol or drug dependence, either active or in remission, is for the treatment of pain requiring opiate agonist analgesia. Patients receiving opiate substitution therapy for opiate substance abuse will have increased tolerance to the analgesic effects of opiate agonists used for acute pain, and will require higher and more frequent dosing to control their pain. Opiate substitution therapy does not adequately treat pain.

    Head trauma, increased intracranial pressure

    Patients with head trauma or with increased intracranial pressure should be given acetaminophen; codeine with extreme caution, because these drugs can make it difficult to evaluate neurologic parameters. Hypoventilation due to the codeine component can produce cerebral hypoxia and raise CSF pressure, exaggerating the injury.

    Cardiac arrhythmias, cardiac disease, hypotension, hypovolemia

    Opiate agonists, such as codeine, produce cholinergic side effects (by stimulating medullary vagal nuclei) causing bradycardia and vasovagal syncope, and induce the release of histamine, causing peripheral vasodilatation and orthostatic hypotension. These effects can cause problems in patients with cardiac disease. Acetaminophen; codeine should be used with caution in patients with cardiac arrhythmias, hypotension, or hypovolemia.

    Labor, obstetric delivery, pregnancy

    Acetaminophen; codeine is classified as FDA pregnancy risk category C drug. No well-controlled studies in pregnant women have been performed. Some experts suggest increased risk of codeine if used for prolonged periods or at high doses near term. Newborns whose mothers have been taking acetaminophen; codeine chronically may show some respiratory depression and/or withdrawal symptoms at birth or within a few days. Higher doses and doses administered close to obstetric delivery may also increase the risk for respiratory depression in the newborn. Newborns of mothers who receive acetaminophen; codeine during labor or delivery should be observed for signs of respiratory depression. Acetaminophen; codeine should be avoided during labor if delivery of a premature newborn is expected. No overall increase in fetal mortality, as determined by pregnancy outcomes of mothers that overdosed on various amounts of acetaminophen, was apparent amongst 300 women. Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 babies exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. Of 67 babies exposed to an overdose of a combination acetaminophen product, 51 were normal, 3 had malformations, 2 were spontaneously aborted (late fetal deaths), and 11 were electively terminated. None of the babies with malformations were exposed during the first trimester, but all of the spontaneous abortions and one of the late fetal deaths were subsequent to first trimester exposure.

    Breast-feeding

    Avoid acetaminophen; codeine use in breast-feeding women; it is distributed into breast milk at varying degrees depending upon the dose. Codeine is metabolized to morphine, which is also distributed into breast milk. Alternative analgesics considered to be usually compatible with breast-feeding by the AAP include acetaminophen, ibuprofen, and morphine. Breast-fed babies of women who quickly metabolize codeine (ultra-rapid metabolizer) may ingest dangerous amounts of morphine. A healthy, 13-day-old breastfed baby died from a morphine overdose; the baby's blood morphine concentration was 70 ng/mL. The mother was taking codeine 30 mg and acetaminophen 500 mg tablets. The mother initially took 2 tablets every 12 hours, but she took half of this dose from day 2 to 14 because of somnolence and constipation. She stored her milk on day 10 because of poor neonatal feeding; the morphine concentration in the milk was 87 ng/mL. She was determined by genetic testing to be an ultra-rapid metabolizer of codeine (heterozygous for a CYP2D6*2A allele with CYP2D6*2x2 gene duplication). Ultra-rapid metabolizers have a specific CYP2D6 genotype and may change codeine to morphine more rapidly and completely than other people. Ultra-rapid metabolizers are more likely to have higher than normal blood and breast milk morphine concentrations after taking codeine. Ultra-rapid metabolism has only been reported as a problem with codeine, although ultra-rapid metabolism has the potential to affect other narcotics. Too much of any narcotic in breast milk can be fatal to a nursing baby. The estimated number of ultra-rapid metabolizers varies among different population groups from less than 1 per 100 people up to 28 per 100 people. Although a genetic test to identify ultra-metabolizers is available, the risk of having an adverse event when taking codeine is not known. The test result alone may not correctly predict if a mother's milk will have too much morphine if she ingests codeine. Acetaminophen also crosses into breast milk, with a concentration ranging from 0.1% to 1.85% of the maternal dose. According to previous American Academy of Pediatrics (AAP) recommendations, acetaminophen is usually compatible with breast-feeding and it has not been associated with any observable changes in nursing babies of mothers that took acetaminophen while breast feeding. If acetaminophen; codeine use by a breast-feeding mother is desired, prescribe the lowest dose for the shortest amount of time to relieve pain or cough. Also, educate nursing patients about the potential risks and the signs of morphine overdose in themselves and in their babies. Instruct patients to immediately call their physician or get emergency help if they are extremely sleepy, confused, or have shallow breathing or severe constipation or if the baby shows signs of increased sleepiness (more than usual), difficulty breast-feeding, difficulty breathing, or limpness. Acetaminophen; codeine should not be used chronically during breast-feeding, as withdrawal symptoms may occur in the baby when the mother stops chronic acetaminophen; codeine therapy. Healthcare providers and other individuals are encouraged to report any acetaminophen; codeine side effects to the FDA by calling 1-800-332-1088.

    Bladder obstruction, oliguria, prostatic hypertrophy, renal disease, renal impairment, urethral stricture, urinary retention

    Codeine 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. Drug accumulation or prolonged duration of action can occur in patients with renal impairment, renal failure, or renal disease. Three patients, a 25-year-old male, a 65-year-old woman, and a 75-year-old male, with normal hepatic function and chronic renal failure (on hemodialysis) developed narcosis a few days after getting codeine 60 mg up to 4 times a day. In addition, chronic acetaminophen administration should be avoided in patients with underlying renal disease; however it may be used for episodic pain. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with renal impairment may require lower doses and/or less frequent dosing intervals.

    Geriatric

    Geriatric patients are more sensitive to adverse reactions from opiate agonists such as codeine; especially sedation and respiratory depression probably as a result of altered distribution of the drug and decreased elimination. Initial doses of opiate agonists may need to be reduced and doses should be carefully titrated taking into account analgesic effects and adverse reactions. According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these populations, with the exception of pain management due to recent fractures or joint replacement, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk.

    Adenoidectomy, children, infants, neonates, obesity, respiratory infection, sleep apnea, tonsillectomy

    Acetaminophen; codeine is contraindicated for the treatment of pain in neonates, infants, and children younger than 12 years. The use of acetaminophen; codeine for postoperative pain management in pediatric patients of all ages after a tonsillectomy and/or adenoidectomy is also contraindicated. The American Academy of Pediatrics (AAP) recommends against the use of codeine in all pediatric patients for any indication. Do not use acetaminophen; codeine in pediatric patients who have obesity or conditions which may increase the risk of serious breathing problems (e.g., obstructive sleep apnea, severe lung disease, asthma, respiratory infection). Codeine metabolism is highly variable and unpredictable, particularly in children younger than 12 years; therapeutic response to recommended doses can range from lack of effect in poor metabolizers to fatality in ultra-rapid metabolizers. Ultra-rapid metabolizers are more likely to convert codeine to morphine quickly, leading to excessive morphine blood concentrations that can result in fatal respiratory depression. Because some children who are normal metabolizers can convert codeine to morphine at rates similar to ultra-metabolizers, this concern extends to all pediatric patients.

    Anemia, G6PD deficiency

    Patients with G6PD deficiency who overdose with acetaminophen; codeine may be at increased risk for drug-induced hemolysis due to the acetaminophen component. During acetaminophen overdose, cyanosis may not be apparent in patients with pre-existing anemia, in spite of dangerously high blood concentrations of methemoglobin.

    Bone marrow suppression, immunosuppression, infection

    Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen; codeine in patients who have bone marrow suppression or immunosuppression.

    Driving or operating machinery

    Any patient receiving acetaminophen; codeine should be warned about the possibility of sedation and to use caution when driving or operating machinery.

    Asian patients, Black patients, Caucasian patients, Hispanic patients

    When prescribing acetaminophen; codeine, consider the race-related prevalence of altered codeine metabolism, including that of Asian patients, Black patients, Caucasian patients, Hispanic patients, and Middle Eastern patients. As codeine is metabolized to morphine via CYP2D6, inter-patient variances in CYP2D6 function may impact the analgesic or toxic effects of codeine. Patients with a deficiency of CYP2D6, those with low to non-functional CYP2D6 phenotypes, or those receiving inhibitors of this isoenzyme are poor metabolizers of codeine. Such patients may not adequately convert codeine to morphine and may not experience the expected analgesic response to codeine. Approximately 7—10% of Caucasian patients are poor CYP2D6 metabolizers. In contrast, some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*1/*1xN or *1/*2xN genotype and are at increased risk of toxicity. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5—1% in Chinese, Japanese, and Hispanic patients; 1—10% in Caucasian patients; 3—28% in Black patients (3% in African Americans and 16—28% in North African and Ethiopians); and 16—28% of Arab patients. Data are not available for other ethnic groups. Ultra-rapid metabolizers convert codeine to morphine more rapidly and completely than other people. Higher than expected serum morphine concentrations occur due to the rapid conversion, and serious toxicity such as extreme sedation, confusion, and apnea may occur. In addition, the breast milk of women who are ultra-rapid metabolizers taking codeine may also contain high concentrations of morphine, which may put a nursing infant at risk for toxic adverse effects.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use codeine with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

    MAOI therapy

    Use of codeine is contraindicated in patients who are receiving or who have received MAOI therapy within the past 14 days. Additive CNS depression, drowsiness, dizziness, or hypotension may occur.

    ADVERSE REACTIONS

    Severe

    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal papillary necrosis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known

    Moderate

    tolerance / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    constipation / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hypoprothrombinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    dysphoria / Early / Incidence not known
    euphoria / Early / Incidence not known
    hyperamylasemia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known

    Mild

    nausea / Early / 19.0-25.0
    vomiting / Early / 7.0-24.0
    headache / Early / 7.0-7.0
    abdominal pain / Early / 5.0-5.0
    pruritus / Rapid / 0-5.0
    anorexia / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    restlessness / Early / Incidence not known
    dizziness / Early / Incidence not known
    purpura / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    syncope / Early / Incidence not known
    flushing / Rapid / Incidence not known
    miosis / Early / Incidence not known
    amenorrhea / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known

    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.
    Acarbose: (Minor) It has been suggested by in vitro and in vivo animal studies that acarbose augments the activity of the hepatic isoenzyme CYP2E1, which is responsible for metabolism of acetaminophen to its toxic reactive metabolite. Patients should avoid the combination of acarbose with acetaminophen and ethanol until more is known about the potential for clinically significant interactions.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Acetaminophen; Butalbital: (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.
    Acetaminophen; Butalbital; Caffeine: (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.
    Acetaminophen; Butalbital; Caffeine; Codeine: (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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (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.
    Acetaminophen; Hydrocodone: (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; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as codeine. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of mu-receptor opiate agonists and reduce analgesic effects of codeine. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Tramadol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
    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.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    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 may 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; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amiodarone: (Minor) Amiodarone inhibits CYP2D6 and may interfere with the conversion of codeine to the active metabolite, morphine. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with any other drugs that inhibit CYP2D6.
    Amitriptyline: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amobarbital: (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: (Moderate) Concomitant use of central nervous system (CNS) depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Examples of drugs associated with CNS depression include amoxapine. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Amprenavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Amyl Nitrite: (Moderate) Administration of nitrates such as amyl nitrite to patients receiving other hypotension-producing agents, such as opiate agonists, can cause additive hypotensive or orthostatic effects.
    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.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
    Aprepitant, Fosaprepitant: (Major) Use caution if codeine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in codeine-related adverse effects, including over-sedation, for several days after administration of a multi-day aprepitant regimen. Codeine is a CYP3A4 substrate. 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 codeine. 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. (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.
    Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and codeine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased codeine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including opiate agonists.
    Aspirin, ASA: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy. (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: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy. (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; Dihydrocodeine: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Dipyridamole: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Omeprazole: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression. (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Aspirin, ASA; Pravastatin: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Atazanavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Atazanavir; Cobicistat: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response. (Moderate) The pharmacologic activity of codeine may be altered with the use of cobicistat which is a CYP3A4 and CYP2D6 inhibitor. The pharmacological activity of codeine is due to its conversion to morphine via the cytochrome CYP2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with drugs that inhibit CYP2D6. The CYP3A4 pathway is also an important metabolic clearance route for codeine.
    Atenolol; Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Atracurium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Atropine; Difenoxin: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
    Atropine; Diphenoxylate: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (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.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azilsartan; Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Azole antifungals: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Baclofen: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Barbiturates: (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 Alkaloids; Ergotamine; Phenobarbital: (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.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Bendroflumethiazide; Nadolol: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Benzonatate: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    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.
    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. (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.
    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. (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.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering acetaminophen with boceprevir due to an increased potential for acetaminophen-related adverse events. If acetaminophen dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of acetaminophen. Acetaminophen is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated acetaminophen plasma concentrations.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including opiate agonists.
    Brigatinib: (Moderate) Monitor for decreased efficacy of codeine, including signs and symptoms of opioid withdrawal in patients who are physically dependent on codeine, if coadministration with brigatinib is necessary. Codeine is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of codeine may decrease.
    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; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Brompheniramine; Guaifenesin; Hydrocodone: (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.
    Brompheniramine; Hydrocodone; 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.
    Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Buprenorphine; Naloxone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as codeine. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Bupropion: (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. An opiate antagonist should only be administered to a patient taking codeine with clinically significant respiratory or cardiovascular depression. Also, patients should be opiate-free for at least 7-10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone, and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur. (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Buspirone: (Moderate) Concomitant use of CNS depressants, such as buspirone, can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. If concurrent use of codeine and buspirone is imperative, reduce the dose of one or both drugs.
    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: (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 codeine. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of codeine. 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.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Capsaicin; Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Carbamazepine: (Moderate) Inducers of CYP3A4 such as carbamazepine may induce the hepatic metabolism of opiate agonists, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after opiate therapy has begun in patients who are opiate tolerant. Clinicians should be alert to changes in the effect of the opioid agonist. Opiate doses may need to be increased if carbamazepine is added. Conversely, doses may need to be decreased if carbamazepine is discontinued. (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.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Carbinoxamine; Hydrocodone; 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.
    Carbinoxamine; Hydrocodone; 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.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including opiate agonists.
    Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Ceritinib: (Major) Consider reducing the dose of codeine if coadministration with cobimetinib is necessary; monitor frequently for sedation and respiratory depression. Ceritinib is a CYP3A4 inhibitor and codeine is metabolized by CYP3A4 and CYP2D6. Coadministration with inhibitors of CYP3A4 may increase codeine plasma concentrations with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    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.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing 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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Chloroprocaine: (Minor) Due to the CNS depression potential of all local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Chlorothiazide: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine; Guaifenesin; Hydrocodone; 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.
    Chlorpheniramine; Hydrocodone: (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.
    Chlorpheniramine; Hydrocodone; 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.
    Chlorpheniramine; Hydrocodone; 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.
    Chlorpromazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorzoxazone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    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: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Cinacalcet: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including codeine.
    Cisatracurium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Citalopram: (Moderate) Impairment of CYP2D6 metabolism by citalopram may reduce the conversion of the opiates codeine and hydrocodone to their active forms, thus reducing analgesic efficacy.
    Clarithromycin: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Clomipramine: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Clozapine: (Moderate) Concomitant use of central nervous system depressants, such as clozapine, can potentiate the effects of codeine, which may lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Combining clozapine with opiate agonists may also lead to additive effects on intestinal motility or bladder function, resulting in constipation or urinary retention.
    Cobicistat: (Moderate) The pharmacologic activity of codeine may be altered with the use of cobicistat which is a CYP3A4 and CYP2D6 inhibitor. The pharmacological activity of codeine is due to its conversion to morphine via the cytochrome CYP2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with drugs that inhibit CYP2D6. The CYP3A4 pathway is also an important metabolic clearance route for codeine.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The pharmacologic activity of codeine may be altered with the use of cobicistat which is a CYP3A4 and CYP2D6 inhibitor. The pharmacological activity of codeine is due to its conversion to morphine via the cytochrome CYP2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with drugs that inhibit CYP2D6. The CYP3A4 pathway is also an important metabolic clearance route for codeine.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The pharmacologic activity of codeine may be altered with the use of cobicistat which is a CYP3A4 and CYP2D6 inhibitor. The pharmacological activity of codeine is due to its conversion to morphine via the cytochrome CYP2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with drugs that inhibit CYP2D6. The CYP3A4 pathway is also an important metabolic clearance route for codeine.
    COMT inhibitors: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    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.
    Cyclobenzaprine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Dantrolene: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Darunavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Darunavir; Cobicistat: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response. (Moderate) The pharmacologic activity of codeine may be altered with the use of cobicistat which is a CYP3A4 and CYP2D6 inhibitor. The pharmacological activity of codeine is due to its conversion to morphine via the cytochrome CYP2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with drugs that inhibit CYP2D6. The CYP3A4 pathway is also an important metabolic clearance route for codeine.
    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) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Delavirdine: (Major) Delavirdine may decrease the efficacy of codeine-containing analgesics by inhibiting the conversion of codeine to morphine via CYP2D6. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with any other drugs that inhibit CYP2D6, such as delavirdine.
    Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desipramine: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Desloratadine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    Desloratadine; Pseudoephedrine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    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.
    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 an opiate agonist is initiated in a patient taking deutetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. 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.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with opiate agonists likely to lead to an enhancement of CNS depression.
    Dexpanthenol: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.
    Dextromethorphan; Quinidine: (Moderate) Quinidine is known to inhibit cytochrome P450 2D6. Codeine is metabolized via this pathway. By interfering with the hepatic conversion of codeine to morphine, quinidine reduces the amount of circulating morphine. The analgesic response to codeine is thus diminished.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    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.
    Diphenhydramine; Hydrocodone; 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.
    Doxacurium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Doxepin: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Dronabinol, THC: (Moderate) Concomitant use of opiate agonists and other CNS depressants such as dronabinol, THC may result in respiratory depression, CNS depression, and/or hypotension. Prior to concurrent use of opiate agonists in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment is necessary, reduce the dose of 1 or both drugs. When levorphanol is used with dronabinol, reduce the initial levorphanol dose by approximately 50% or more.
    Droperidol: (Major) Central nervous system (CNS) depressants have additive or potentiating effects with droperidol. Following administration of droperidol, the dose of the other CNS depressant should be reduced. Furthermore, according to the manufacturer, ethanol abuse and the use of benzodiazepines and intravenous opiates are risk factors for the development of prolonged QT syndrome in patients receiving droperidol.
    Drospirenone; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Efavirenz: (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: (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.
    Elbasvir; Grazoprevir: (Moderate) Administering codeine with elbasvir; grazoprevir may result in elevated codeine plasma concentrations. Codeine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    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. (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Opiate agonists are a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of the opiate agonist is possible. Monitor patients for adverse reactions if eltrombopage is administered with an opiate agonist.
    Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as opiate agonists. 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. In addition, the CYP3A4 metabolism of some opiate agonists may be inhibited by eluxadoline. Although the CYP3A4 inhibitory effects of eluxadoline have not been definitively established, the manufacturer recommends caution when administering eluxadoline concurrently with CYP3A4 substrates that have a narrow therapeutic index, such as fentanyl and alfentanil. Closely monitor for increased side effects if these drugs are administered together. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Enflurane: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Erythromycin: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Erythromycin; Sulfisoxazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Escitalopram: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with any other drugs that inhibit CYP2D6. Escitalopram modestly inhibits metabolism via the CYP2D6 pathway.
    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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Eszopiclone: (Moderate) Concomitant use of eszopiclone with codeine can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of codeine and/or eszopiclone may be recommended. Monitor patients for sedation and respiratory depression.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol. (Major) The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume ethanol. Acute or chronic ethanol use increases acetaminophen-induced hepatotoxicity by inducing cytochrome P450 CYP 2E1 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 ethanol regularly.
    Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Desogestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Etonogestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norgestimate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norgestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethotoin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
    Etomidate: (Major) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    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.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as opiate agonists, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluconazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Fluoxetine: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    Fluoxetine; Olanzapine: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression, including opiate agonists. (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    Fluphenazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Fosamprenavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Fosphenytoin: (Moderate) In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Gabapentin: (Moderate) Pain medications that contain opiate agonists may intensify CNS depressive adverse effects seen with gabapentin use, such as drowsiness or dizziness. Patients should limit activity until they are aware of how coadministration affects them.
    Gefitinib: (Moderate) Monitor for decreased efficacy of codeine if gefitinib and codeine are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of codeine to morphine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as codeine.
    Guaifenesin; Hydrocodone: (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.
    Guaifenesin; Hydrocodone; 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.
    Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as opiate agonists, when administered concomitantly.
    Guanfacine: (Moderate) Central-acting adrenergic agonists like guanfacine have CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Guselkumab: (Moderate) Clinically relevant drug interactions may occur when guselkumab is administered with sensitive substrates of CYP2D6, such as codeine. Monitor codeine concentrations if guselkumab is initiated or discontinued; the codeine dose may need to be adjusted. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP2D6 could be normalized during guselkumab administration.
    Haloperidol: (Moderate) Haloperidol inhibits CYP2D6 and may decrease the conversion of codeine to morphine, decreasing its effectiveness.
    Halothane: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Homatropine; Hydrocodone: (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.
    Hydantoins: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Opiate agonists like codeine may potentiate orthostatic hypotension when given concomitantly with spironolactone. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrocodone: (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.
    Hydrocodone; Ibuprofen: (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.
    Hydrocodone; 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.
    Hydrocodone; Potassium Guaiacolsulfonate: (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.
    Hydrocodone; Potassium Guaiacolsulfonate; 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.
    Hydrocodone; 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.
    Hydromorphone: (Major) Concomitant use of hydromorphone with other central nervous system (CNS) depressants, such as other opiate agonists, can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Hydroxyprogesterone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2A6 isoenzymes. The metabolism of drugs metabolized by CYP2A6, such as acetaminophen may be increased during treatment with hydroxyprogesterone.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Iloperidone: (Moderate) Concomitant use of iloperidone with other centrally-acting medications such as opiate agonists, may increase both the frequency and the intensity of adverse effects including drowsiness, sedation, and dizziness.
    Imatinib, STI-571: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with any other drugs that inhibit CYP2D6 including imatinib.
    Imipramine: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Indinavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Insulin Degludec; Liraglutide: (Minor) Liraglutide did not change the AUC of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after a dose of liraglutide 1.8 mg at steady state; however, the Cmax of acetaminophen was decreased by 31% and the median Tmax of acetaminophen was delayed up to 15 minutes. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If acetaminophen and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered acetaminophen effect.
    Insulin Glargine; Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with acetaminophen may result in increased serum concentrations of acetaminophen. Acetaminophen is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Isoflurane: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Isoniazid, INH: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Agents which induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as rifampin, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. (Moderate) CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Isoniazid, INH; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Agents which induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as rifampin, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. (Moderate) CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Itraconazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Ketamine: (Moderate) The use of ketamine with other CNS depressants, including opiate agonists, potentiate CNS depression and/or increase the risk of developing respiratory depression.
    Ketoconazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Lactobacillus: (Moderate) Concurrent use of antidiarrheals and opiate agonists, can lead to severe constipation and possibly additive CNS depression. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    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.
    Lamotrigine: (Major) Acetaminophen can be hepatotoxic, and lamotrigine appears to be a potential cause of progressive and fatal hepatotoxicity despite drug discontinuation. A 35 year-old developed fulminant liver failure possibly caused by lamotrigine. She was taking several other drugs including acetaminophen. In a randomized, single-dose study, the serum half-life of lamotrigine after a 300 mg dose decreased by 15% and the area under the plasma concentration-time curve decreased by 20% when given with acetaminophen 900 mg 3 times a day as compared with administration of lamotrigine with placebo. As the lamotrigine maximum serum concentration (Cmax) and time to Cmax was similar between the groups, and the lamotrigine renal clearance increased by 7%, acetaminophen appears to enhance removal of lamotrigine from the circulation.
    Lanthanum Carbonate: (Minor) The manufacturer recommends that oral compounds known to interact with antacids, such as acetaminophen, should not be taken within 2 hours of dosing with lanthanum carbonate.
    Levobupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lincosamides: (Moderate) Lincosamides, which have been shown to exhibit neuromuscular blocking action, can enhance the effects of opiate agonists if used concomitantly, enhancing respiratory depressant effects. They should be used together with caution and the patient carefully monitored.
    Linezolid: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Linezolid is a reversible, non-selective inhibitor of MAO. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Liraglutide: (Minor) Liraglutide did not change the AUC of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after a dose of liraglutide 1.8 mg at steady state; however, the Cmax of acetaminophen was decreased by 31% and the median Tmax of acetaminophen was delayed up to 15 minutes. The mechanism of the interaction is not known, nor is the clinical significance of this potential interaction. If acetaminophen and liraglutide are co-prescribed, it may be prudent to initially monitor the patient for altered acetaminophen effect.
    Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
    Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day PO for >= 3 days/week). The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Loperamide: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Loperamide; Simethicone: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Lopinavir; Ritonavir: (Moderate) 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) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    Loratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as opiate agonists. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Lumacaftor; Ivacaftor: (Minor) Concomitant use of codeine and lumacaftor; ivacaftor may alter the response to codeine; if used together, monitor analgesic activity and adverse drug reactions. Lumacaftor is a strong CYP3A inducer. Codeine relies upon CYP3A-mediated N-demethylation to convert to its inactive metabolite norcodeine. Induction of codeine through the CYP3A pathway may increase plasma concentrations of norcodeine.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as opiate agonists.
    Magnesium 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.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Mephobarbital: (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.
    Mepivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mepivacaine; Levonordefrin: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meprobamate: (Moderate) Concomitant use of meprobamate with codeine can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of codeine and/or meprobamate may be recommended. Monitor patients for sedation and respiratory depression.
    Mesoridazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Methadone: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone 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. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Methocarbamol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Methohexital: (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.
    Methyclothiazide: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly.
    Methylene Blue: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Metoclopramide: (Moderate) Opiate agonists antagonize GI motility and can decrease the gastroprokinetic effects of metoclopramide.
    Metolazone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Metyrapone: (Major) Coadministration of metyrapone and acetaminophen may result in acetaminophen toxicity. Acetaminophen glucuronidation is inhibited by metyrapone. It may be advisable for patients to avoid acetaminophen while taking metyrapone. (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as opiate agonists, should be used with caution. Additive drowsiness and/or dizziness is possible. Also, hydrocodone is metabolized by CYP3A4. Metyrapone, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with metyrapone.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
    Midazolam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as codeine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Moderate) Concomitant use of CNS depressants, such as mirtazapine, can potentiate the effects of codeine, potentially leading to respiratory depression, CNS depression, sedation, or hypotensive responses. In some cases, a dose reduction of codeine or the second agent may be warranted.
    Mitotane: (Major) Use caution if mitotane and codeine are used concomitantly, and monitor for decreased efficacy of codeine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and codeine is a CYP3A4 substrate. In vitro studies have shown no effect of carbamazepine and phenytoin (strong CYP3A inducers) on the conversion of codeine to morphine. However, CYP450 induction may increase the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Mivacurium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Molindone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as molindone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or molindone is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Monoamine oxidase inhibitors: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Morphine: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Morphine; Naltrexone: (Major) Concomitant use of morphine with codeine can potentiate the effects of morphine on respiration, blood pressure, and alertness. Profound sedation and coma may also occur. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of morphine and/or codeine is recommended; for extended-release morphine products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Nabilone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as nabilone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Nalbuphine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as codeine. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects of acetaminophen; codeine. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Naloxone: (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. An opiate antagonist should only be administered to a patient taking codeine with clinically significant respiratory or cardiovascular depression. Also, patients should be opiate-free for at least 7-10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone, and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
    Nefazodone: (Moderate) Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Nelfinavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
    Neuromuscular blockers: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Nilotinib: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with opiate agonists.
    Nortriptyline: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Octreotide: (Moderate) Octreotide can cause additive constipation with opiate agonists such as codeine. 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. Monitor patients during concomitant use.
    Olanzapine: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression, including opiate agonists.
    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) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Omeprazole; 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.
    Oritavancin: (Moderate) Codeine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of codeine may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    Osimertinib: (Minor) Use caution if coadministration of osimertinib and acetaminophen is necessary, due to the risk of decreased acetaminophen exposure. Although acetaminophen is primarily metabolized via glucuronidation and sulfate conjugation, it is also a minor CYP1A2 substrate; osimertinib is a CYP1A2 inducer in vitro. Coadministration may decrease the efficacy of acetaminophen.
    Oxazepam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Oxcarbazepine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as oxcarbazepine, 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.
    Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Oxymorphone: (Major) Concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Respiratory depression, hypotension, profound sedation, or coma may result from combination therapy. Prior to concurrent use of oxymorphone 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. Oxymorphone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxymorphone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Slowly titrate the dose as necessary for adequate pain relief and monitor for sedation or respiratory depression.
    Palbociclib: (Moderate) Use caution if coadministration of palbociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Paliperidone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Pancuronium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Papaverine: (Moderate) Papaverine is a benzylisoquinoline alkaloid of opium and may have synergistic effects with opiate agonists. Concurrent use of papaverine with potent CNS depressants could lead to enhanced sedation.
    Paroxetine: (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Peginterferon Alfa-2b: (Moderate) Peginterferon alfa-2b inhibits CYP2D6. Exposure of drugs metabolized by CYP2D6 such as codeine may be increased when co-administered with peginterferon alfa-2b. The pharmacological activity of codeine is due to its conversion to morphine via the cytochrome CYP2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with drugs that inhibit CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Pegvisomant: (Moderate) In clinical trials, patients taking opiate agonists often required higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opiate agonists. The mechanism of this interaction is unknown.
    Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as codeine. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of mu-receptor opiate agonists and reduce analgesic effects of codeine. 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.
    Pentazocine; Naloxone: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as codeine. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of mu-receptor opiate agonists and reduce analgesic effects of codeine. 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. (Major) Naloxone can antagonize the therapeutic efficacy of codeine in addition to precipitating withdrawal symptoms in patients who are physically dependent on opiate drugs including codeine.
    Pentobarbital: (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.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as opiate agonists.
    Perphenazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Perphenazine; Amitriptyline: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted. (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Phenelzine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Phenobarbital: (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.
    Phenothiazines: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Phenytoin: (Moderate) In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Pimozide: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as pimozide, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Pneumococcal Vaccine, Polyvalent: (Moderate) Concomitant administration of antipyretics, such as acetaminophen, may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen.
    Posaconazole: (Moderate) Posaconazole and acetaminophen should be coadministered with caution due to an increased potential for acetaminophen-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of acetaminophen. These drugs used in combination may result in elevated acetaminophen plasma concentrations, causing an increased risk for acetaminophen-related adverse events. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Pramipexole: (Moderate) The use of opiate agonists in combination with pramipexole may increase the risk of clinically significant sedation via a pharmacodynamic interaction.
    Pramlintide: (Major) Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications with the potential to slow GI motility, such as opiate agonists, should be used with caution, if at all, with pramlintide until more data are available from the manufacturer. Monitor blood glucose. (Minor) Because pramlintide has the potential to delay the absorption of concomitantly administered medications, medications should be administered at least 1 hour before or 2 hours after pramlintide injection when the rapid onset of a concomitantly administered oral medication is a critical determinant of effectiveness (i.e., analgesics).
    Pregabalin: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Examples of drugs associated with CNS depression include pregabalin. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Prilocaine: (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 may 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. (Minor) Prilocaine and acetaminophen each individually can cause methemoglobinemia. Patients treated with prilocaine who are receiving acetaminophen concurrently are at greater risk for developing methemoglobinemia.
    Prilocaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic may 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. (Minor) Prilocaine and acetaminophen each individually can cause methemoglobinemia. Patients treated with prilocaine who are receiving acetaminophen concurrently are at greater risk for developing methemoglobinemia.
    Primidone: (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.
    Procarbazine: (Moderate) Opiate agonists may cause additive sedation or other CNS effects when given in combination with procarbazine.
    Prochlorperazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Propafenone: (Minor) Concomitant use of propafenone with codeine-containing products may decrease the metabolism of codeine to morphine by inhibiting cytochrome CYP2D6; varying degrees of analgesia may be seen.
    Protease inhibitors: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Protriptyline: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Quazepam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Quetiapine: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants such as quetiapine can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Quinidine: (Moderate) Quinidine is known to inhibit cytochrome P450 2D6. Codeine is metabolized via this pathway. By interfering with the hepatic conversion of codeine to morphine, quinidine reduces the amount of circulating morphine. The analgesic response to codeine is thus diminished.
    Quinine: (Minor) The activity of codeine is due to its conversion to morphine via the cytochrome P450 2D6 hepatic isoenzyme. Quinine inhibits CYP2D6 and may decrease the conversion of codeine to morphine; a corresponding decrease in analgesia is seen.
    Ranolazine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with ranolazine which inhibits CYP2D6. Monitor therapeutic response during coadministration.
    Rapacuronium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Rasagiline: (Severe) Rasagiline is contraindicated for use with codeine due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of rasagiline and the initiation of codeine.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in an increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Ribociclib is a moderate CYP3A4 inhibitor. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with codeine is necessary, as the systemic exposure of codeine may be increased resulting in an increase in treatment-related adverse reactions including sedation and respiratory depression; adjust the dose of codeine if necessary. Ribociclib is a moderate CYP3A4 inhibitor. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norocodeine; norcodeine does not have analgesic properties. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
    Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Rifampin: (Moderate) Agents which induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as rifampin, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. (Moderate) CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Risperidone: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as risperidone, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    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) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Rocuronium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Rolapitant: (Major) Use caution if codeine and rolapitant are used concurrently, and monitor for decreased efficacy of codeine. Codeine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; CYP2D6 is partially responsible for the metabolism of codeine to morphine. The inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Ropinirole: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as ropinirole can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Ropivacaine: (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 may 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.
    Safinamide: (Severe) Safinamide is contraindicated for use with codeine due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of safinamide and the initiation of codeine.
    Salsalate: (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.
    Saquinavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Secobarbital: (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.
    Sedating H1-blockers: (Moderate) Concomitant use of codeine with sedating H1 blockers can potentiate respiratory depression and sedation. In addition, chlorpheniramine and diphenhydramine inhibit CYP2D6, an enzyme responsible for the metabolism of codeine. Monitor patients on these combinations closely.
    Selegiline: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Sertraline: (Minor) The activity of codeine is due to its conversion to morphine via the cytochrome P450 CYP2D6 hepatic isoenzyme. The analgesic activity of codeine may be reduced when it is combined with drugs that inhibit CYP2D6, such as sertraline.
    Sevoflurane: (Moderate) Concurrent use of sevoflurane with opiate agonists such as codeine can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Sildenafil: (Moderate) Prolonged erections have been reported in two patients taking sildenafil with dihydrocodeine. Although more data are needed, use caution when prescribing opiate agonists and sildenafil concomitantly.
    Skeletal Muscle Relaxants: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants.
    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.
    Sodium Oxybate: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with opiate agonists.
    Solifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as solifenacin. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Spironolactone: (Moderate) Opiate agonists like codeine may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    St. John's Wort, Hypericum perforatum: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
    Succinylcholine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Sulfinpyrazone: (Minor) Sulfinpyrazone can induce hepatic oxidative microsomal enzymes and the drug has been shown to increase acetaminophen clearance by roughly 23%. Theoretically, it is thought that the induction of acetaminophen metabolism by sulfinpyrazone may increase the risk of acetaminophen hepatotoxicity due to the formation of increased amounts of toxic acetaminophen metabolites, but there is no confirmatory evidence.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tapentadol: (Major) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants, including other opiate agonists. Severe hypotension, profound sedation, coma, or respiratory depression may occur. Prior to concurrent use of tapentadol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If an opiate agonist is used concurrently with tapentadol, a reduced dosage of tapentadol and/or the opiate agonist is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering acetaminophen with telaprevir due to an increased potential for acetaminophen-related adverse events. If acetaminophen dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of acetaminophen. Acetaminophen is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated acetaminophen plasma concentrations.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and codeine is necessary, as the systemic exposure of codeine and resultant morphine may be decreased resulting in reduced efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If these drugs are used together, monitor patients for suboptimal efficacy of codeine or withdrawal; consider increasing the dose of codeine if necessary. After stopping telotristat ethyl, monitor for sedation and respiratory depression at frequent intervals and consider a codeine dose reduction if necessary. Codeine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. The concomitant use of codeine with CYP3A4 inducers can decrease codeine levels, increase norcodeine levels, and decrease metabolism via 2D6, subsequently resulting in lower morphine levels. (Moderate) Use telotristat ethyl and CYP3A4 substrates, such as acetaminophen, together with caution; the systemic exposure of acetaminophen may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of acetaminophen; consider increasing the dose of acetaminophen if necessary. The systemic exposure of a sensitive CYP3A4 substrate was significantly decreased (by 48%) when it was coadministered with telotristat ethyl. The mechanism of this drug interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Terbinafine: (Minor) The activity of codeine is due to its conversion to morphine via the cytochrome P450 2D6 hepatic isoenzyme. Terbinafine may interfere with the conversion of codeine to morphine; a corresponding decrease in analgesia may be seen.
    Tetrabenazine: (Moderate) Additive effects are possible when tetrabenazine is combined with other drugs that cause CNS depression. Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as opiate agonists, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Tetracaine: (Major) Due to the central nervous system depression potential of all local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists. Excitation or depression of the CNS may be the first manifestation of CNS toxicity. Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of CNS toxicity. After each local anesthetic injection, careful and constant monitoring of ventilation adequacy, cardiovascular vital signs, and the patient's state of consciousness is advised.
    Thalidomide: (Major) Avoid the concomitant use of thalidomide with opiate agonists; antihistamines; antipsychotics; anxiolytics, sedatives, and hypnotics; and other central nervous system depressants due to the potential for additive sedative effects.
    Thiazide diuretics: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Thiethylperazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Thiopental: (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.
    Thioridazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as opiate agonists. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Tioconazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Tipranavir: (Moderate) The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
    Tizanidine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking skeletal muscle relaxants. (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
    Tobacco: (Moderate) Tobacco smoking induces the cytochrome P450 isoenzyme CYP1A2 and may potentially increase the risk for acetaminophen-induced hepatotoxicity during overdose via enhanced generation of acetaminophen's hepatotoxic metabolite, NAPQI. In one study, current tobacco smoking was found to be very frequent in patients admitted with acetaminophen poisoning. Tobacco smoking appears to be an independent risk factor of severe hepatotoxicity, acute liver failure and death following acetaminophen overdose.
    Tolcapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Tolterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when codeine is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of codeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Tramadol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
    Tranylcypromine: (Severe) Codeine use is contraindicated in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of codeine with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as codeine.
    Trazodone: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    Triazolam: (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 an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. 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 prescribing opiate cough medications in patients taking benzodiazepines.
    Tricyclic antidepressants: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Trifluoperazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like opiate agonists, may potentiate the effects of either trimethobenzamide or the opiate agonist.
    Trimetrexate: (Moderate) Acetaminophen can inhibit oxidative hepatic enzymes responsible for metabolizing trimetrexate. Concurrent use can decrease the clearance of trimetrexate and thus increase its plasma levels.
    Trimipramine: (Moderate) Use of tricyclic antidepressants (TCAs) with codeine may increase the effect of either the TCA or codeine. Concomitant use may potentially lead to increased CNS depression, sedation, respiratory depression, or hypotensive responses. Both TCAs and opiate agonists may produce constipation. Use codeine with caution and in reduced dosages in patients taking TCAs.
    Trospium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when opiate agonists are used concomitantly with an anticholinergic drug, such as trospium. The concomitant use of opiate agonists and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Tubocurarine: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Valerian, Valeriana officinalis: (Moderate) Any substances that act on the CNS may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. The sedative effect may be additive to other drugs with sedative actions, such as the opiate agonists. Consider the patient's use of alcohol or illicit drugs. If valerian is used concurrently with a CNS depressant, a reduced dosage of the CNS depressant may be required, or, the valerian supplement may be discontinued. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Vecuronium: (Moderate) Concomitant use of codeine with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with opiate agonists.
    Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as opiate agonists.
    Voriconazole: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Warfarin: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
    Zaleplon: (Moderate) Concomitant use of zaleplon can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of codeine and/or zaleplon may be recommended. Monitor patients for sedation and respiratory depression.
    Ziconotide: (Moderate) Concurrent use of ziconotide and opiate agonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
    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.
    Ziprasidone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including codeine.
    Zolmitriptan: (Minor) Zolmitriptan can delay the Tmax of acetaminophen by one hour. A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its active metabolite. The interaction between zolmitriptan and acetaminophen is not likely to be clinically significant.
    Zolpidem: (Moderate) Concomitant use of zolpidem can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. Prior to concurrent use, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A reduced dosage of codeine and/or zolpidem may be recommended. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Monitor patients for sedation and respiratory depression.

    PREGNANCY AND LACTATION

    Pregnancy

    Avoid acetaminophen; codeine use in breast-feeding women; it is distributed into breast milk at varying degrees depending upon the dose. Codeine is metabolized to morphine, which is also distributed into breast milk. Alternative analgesics considered to be usually compatible with breast-feeding by the AAP include acetaminophen, ibuprofen, and morphine. Breast-fed babies of women who quickly metabolize codeine (ultra-rapid metabolizer) may ingest dangerous amounts of morphine. A healthy, 13-day-old breastfed baby died from a morphine overdose; the baby's blood morphine concentration was 70 ng/mL. The mother was taking codeine 30 mg and acetaminophen 500 mg tablets. The mother initially took 2 tablets every 12 hours, but she took half of this dose from day 2 to 14 because of somnolence and constipation. She stored her milk on day 10 because of poor neonatal feeding; the morphine concentration in the milk was 87 ng/mL. She was determined by genetic testing to be an ultra-rapid metabolizer of codeine (heterozygous for a CYP2D6*2A allele with CYP2D6*2x2 gene duplication). Ultra-rapid metabolizers have a specific CYP2D6 genotype and may change codeine to morphine more rapidly and completely than other people. Ultra-rapid metabolizers are more likely to have higher than normal blood and breast milk morphine concentrations after taking codeine. Ultra-rapid metabolism has only been reported as a problem with codeine, although ultra-rapid metabolism has the potential to affect other narcotics. Too much of any narcotic in breast milk can be fatal to a nursing baby. The estimated number of ultra-rapid metabolizers varies among different population groups from less than 1 per 100 people up to 28 per 100 people. Although a genetic test to identify ultra-metabolizers is available, the risk of having an adverse event when taking codeine is not known. The test result alone may not correctly predict if a mother's milk will have too much morphine if she ingests codeine. Acetaminophen also crosses into breast milk, with a concentration ranging from 0.1% to 1.85% of the maternal dose. According to previous American Academy of Pediatrics (AAP) recommendations, acetaminophen is usually compatible with breast-feeding and it has not been associated with any observable changes in nursing babies of mothers that took acetaminophen while breast feeding. If acetaminophen; codeine use by a breast-feeding mother is desired, prescribe the lowest dose for the shortest amount of time to relieve pain or cough. Also, educate nursing patients about the potential risks and the signs of morphine overdose in themselves and in their babies. Instruct patients to immediately call their physician or get emergency help if they are extremely sleepy, confused, or have shallow breathing or severe constipation or if the baby shows signs of increased sleepiness (more than usual), difficulty breast-feeding, difficulty breathing, or limpness. Acetaminophen; codeine should not be used chronically during breast-feeding, as withdrawal symptoms may occur in the baby when the mother stops chronic acetaminophen; codeine therapy. Healthcare providers and other individuals are encouraged to report any acetaminophen; codeine side effects to the FDA by calling 1-800-332-1088.

    MECHANISM OF ACTION

    Mechanism of Action: Acetaminophen-codeine combination produced analgesia through two different mechanisms of action leading to a synergistic analgesic affect.•Codeine: Codeine is a weak µ-opiate receptor agonist and the majority of its analgesic affect is due to metabolism to morphine. Opiate analgesia is mediated through changes in the perception of pain at the spinal cord and higher levels in the CNS. Opiate analgesics also alter the emotional response to pain. The stimulatory effects of opioids are the result of 'disinhibition' as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The antitussive effect of codeine is due to direct action of codeine in the cough center of the medulla.•Acetaminophen: Acetaminophen acts primarily in the CNS and increases the pain threshold by inhibiting cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2. Acetaminophen weakly inhibits PG synthesis in peripheral tissues, which is the reason for its lack of clinical useful peripheral anti-inflammatory effects. The antipyretic activity of acetaminophen is exerted by blocking the effects of endogenous pyrogen on the hypothalamic heat-regulating center by inhibiting PG synthesis.

    PHARMACOKINETICS

    Acetaminophen; codeine is administered orally. Both acetaminophen and codeine are metabolized in the liver via CYP450 and excreted through the kidney. Administration of other drugs which affect these isoenzymes may affect the efficacy and incidence of adverse reactions from the acetaminophen-codeine combination.
    Codeine: The metabolism of codeine is primarily by glucuronidation with a minor amount of codeine metabolized to morphine via O-demethylation. The metabolism to morphine is mediated by CYP2D6.
    Acetaminophen: Acetaminophen primarily undergoes glucuronidation and sulfate conjugation; however, a small percentage of the dose is metabolized via CYP2E1 and CYP1A2 to a hepatotoxic metabolite. Depletion of glucuronide and sulfate stores due to chronic ethanol use or acute acetaminophen overdose may increase oxidative metabolism of acetaminophen leading to hepatotoxicity.

    Oral Route

    The onset of analgesia is within 30 minutes with peak analgesic effects in about 90 minutes. The duration of analgesia is 3—4 hours.