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    Opioid Antitussive and Expectorant Combinations

    BOXED WARNING

    Asthma, bronchitis, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, emphysema, fever, headache, respiratory depression, tobacco smoking

    Avoid coadministration with other CNS depressants, including alcohol; this combination increases the risk for respiratory depression, low blood pressure, and death. Additionally, codeine; guaifenesin combination products should not be used for persistent or chronic cough such as occurs with tobacco smoking, asthma, chronic obstructive pulmonary disease (COPD), emphysema, or chronic bronchitis or any other condition where cough is associated with excessive secretions, unless under the supervision of a health care professional. Indiscriminate use in these patients may precipitate respiratory insufficiency from suppression of the cough reflex. A recurrent or persistent cough (lasting for more than one week), or a cough accompanied by fever, nausea/vomiting, rash, or persistent headache may be signs of a more serious condition and should be evaluated by a physician.

    DEA CLASS

    OTC, Rx, schedule V, schedule III

    DESCRIPTION

    Codeine is an opiate agonist antitussive agent; guaifenesin is an expectorant
    Used in combination to treat cough
    Codeine metabolism is highly variable and unpredictable; use of codeine-containing products in pediatric patients is not recommended

    COMMON BRAND NAMES

    Allfen CD, Allfen CDX, Antituss AC, Brontex, Cheracol with Codeine, Cheratussin AC, Codefen, Duraganidin NR, Gani-Tuss NR, Guai Co, Guaiatussin AC, Guiatuss AC, Halotussin AC, Iophen C-NR, M-Clear, M-Clear WC, Mar-Cof CG, Mytussin AC, Ninjacof-XG, RelCof C, Robafen AC, Romilar AC, Tussi-Organidin NR, Virtussin AC

    HOW SUPPLIED

    Allfen CD/Allfen CDX/Brontex Oral Tab: 10-300mg, 10-400mg, 20-400mg
    Antituss AC/Brontex/Cheratussin AC/Codefen/Codeine Phosphate, Guaifenesin/Duraganidin NR/Gani-Tuss NR/Guai Co/Guaiatussin AC/Guiatuss AC/Halotussin AC/Iophen C-NR/Mar-Cof CG/Robafen AC/Romilar AC/Tussi-Organidin NR/Virtussin AC Oral Liq: 5mL, 10-100mg, 2.5-75mg, 7.5-225mg
    Antituss AC/Cheratussin AC/Codefen/Codeine Phosphate, Guaifenesin/Duraganidin NR/Gani-Tuss NR/Guai Co/Guaiatussin AC/Guiatuss AC/Halotussin AC/Iophen C-NR/M-Clear WC/Ninjacof-XG/Robafen AC/Romilar AC/Tussi-Organidin NR/Virtussin AC Oral Sol: 5mL, 10-100mg, 6.3-100mg, 8-200mg
    Cheracol with Codeine/Codeine Phosphate, Guaifenesin/Guaiatussin AC/Guiatuss AC/Mytussin AC Oral Syrup: 5mL, 10-100mg
    M-Clear Oral Cap: 9-200mg

    DOSAGE & INDICATIONS

    For the temporary relief of non-productive cough due to minor throat and bronchial irritation as may occur with the common cold, acute bronchitis† or inhaled irritants.
    NOTE: In January 2007, the CDC warned caregivers and healthcare providers of the risk for serious injury or fatal overdose from the administration of cough and cold products to children and infants less than 2 years of age. This warning followed an investigation of the deaths of three (3) infants less than 6 months of age that were attributed to the inadvertent inappropriate use of these products. The symptoms preceding these deaths have not been clearly defined, and there is a lack of conclusive data describing the exact cause of death. The report estimated that 1519 children less than 2 years of age were treated in emergency departments during 2004—2005 for adverse events related to cough and cold medications. In October 2007, the FDA Nonprescription Drug Advisory Committee and the Pediatric Advisory Committee recommended that nonprescription cough and cold products containing pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, brompheniramine, phenylephrine, clemastine, or guaifenesin not be used in children less than 6 years of age. In January 2008, the FDA issued a Public Health Advisory recommending that OTC cough and cold products not be used in infants and children less than 2 years. An official ruling regarding the use of these products in children greater than 2 years has not yet been announced. The FDA recommends that if parents and caregivers use cough and cold products in children greater than 2 years, labels should be read carefully, caution should be used when administering multiple products, and only measuring devices specifically designed for use with medications should be used. While some combination cough/cold products containing these ingredients are available by prescription only and are not necessarily under scrutiny by the FDA, clinicians should thoroughly assess each patient's use of similar products, both prescription and nonprescription, to avoid duplication of therapy and the potential for inadvertent overdose.
    NOTE: Many liquid formulations contain 3—5% alcohol.
    Oral dosage (syrup containing codeine 10 mg and guaifenesin 200 mg per 5 ml; e.g., Tusso-C)
    Adults, Adolescents, and Children >= 12 years

    10 ml PO every 4—6 hours. Do not exceed 60 ml in 24 hours.

    Children 6—11 years

    5 ml PO every 4—6 hours. Do not exceed 30 ml in 24 hours.

    Children 5 years (average 18 kg)

    2.5 ml PO every 4—6 hours. Do not exceed 10 ml in 24 hours.

    Children 3—4 years (average 14—16 kg)

    1.25 ml PO every 4—6 hours. Do not exceed 5 ml in 24 hours.

    Oral dosage (tablets or syrup)
    Adults and Adolescents

    10—20 mg of the codeine component PO every 4—6 hours as needed. Do not exceed 60 mg codeine/dose. The daily dose of codeine and guaifenesin should not exceed 120 mg/day and 2.4 g/day, respectively, or as directed by the prescriber.

    Children

    1—1.5 mg/kg/day of the codeine component PO in divided doses every 4—6 hours as needed. Alternatively, children 6—12 years old may receive 5—10 mg of the codeine component PO every 4—6 hours as needed; do not exceed 60 mg/day of codeine or 1.2 g/day of guaifenesin. Children 2—5 years old can receive 2.5—5 mg of the codeine component PO every 4—6 hours as needed; do not exceed 30 mg/day of codeine or 600 mg/day of guaifenesin.

    Children < 2 years

    Safety and efficacy have not been established.

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: Do not exceed recommended dosage limits for the specific product prescribed; the following are general guidelines:

    Adults

    Codeine 120 mg/day PO with guaifenesin 2.4 g/day PO.

    Elderly

    Codeine 120 mg/day PO with guaifenesin 2.4 g/day PO.

    Adolescents

    Codeine 120 mg/day PO with guaifenesin 2.4 g/day PO.

    Children

    6—12 years: Codeine 60 mg/day PO with guaifenesin 1.2 g/day PO.
    2—5 years: Codeine 30 mg/day PO with guaifenesin 600 mg/day PO.
    < 2 years: Safety and efficacy have not been established.

    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 of the codeine component should be modified depending upon the clinical response and degree of renal impairment; no recommendations are available for guaifenesin.
    CrCl > 50 mL/min: No dosage adjustment needed.
    CrCl 10—50 mL/min: Reduce codeine dosage by 25%.
    CrCl < 10 mL/min: Reduce codeine dosage by 50%.

    ADMINISTRATION

     
    NOTE: This monograph discusses the dosage of codeine; guaifenesin combination products for the relief of cough. Clinicians may wish to consult the individual monographs for more information.

    Oral Administration

    Administer with a full glass of water. May take with food or milk to minimize GI irritation.

    Oral Liquid Formulations

    Use a calibrated measuring device to give an accurate dose of oral syrups.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Allfen CD :
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    Allfen CDX:
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    Antituss AC :
    - Store at room temperature (between 59 to 86 degrees F)
    Brontex:
    - Store at room temperature (between 59 to 86 degrees F)
    Cheracol with Codeine :
    - Avoid exposure to heat
    - Store at room temperature (between 59 to 86 degrees F)
    Cheratussin AC :
    - Store at room temperature (between 59 to 86 degrees F)
    Codefen:
    - Store at room temperature (between 59 to 86 degrees F)
    Dex-Tuss:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Diabetic Tussin C:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Duraganidin NR:
    - Store at room temperature (between 59 to 86 degrees F)
    ExeClear-C :
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Gani-Tuss NR :
    - Store at room temperature (between 59 to 86 degrees F)
    Guai Co:
    - Store at room temperature (between 59 to 86 degrees F)
    Guaiatussin AC:
    - Store at room temperature (between 59 to 86 degrees F)
    Guiatuss AC:
    - Store at room temperature (between 59 to 86 degrees F)
    Halotussin AC :
    - Store at room temperature (between 59 to 86 degrees F)
    Iophen C-NR :
    - Store at room temperature (between 59 to 86 degrees F)
    Mar-Cof CG :
    - Store at room temperature (between 59 to 86 degrees F)
    M-Clear:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    M-Clear WC:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Mytussin AC :
    - Avoid exposure to heat
    - Store at room temperature (between 59 to 86 degrees F)
    Ninjacof-XG:
    - Store at room temperature (between 59 to 86 degrees F)
    RelCof C :
    - Store at room temperature (between 59 to 86 degrees F)
    Robafen AC :
    - Store at room temperature (between 59 to 86 degrees F)
    Romilar AC:
    - Store at room temperature (between 59 to 86 degrees F)
    Tussiden C:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Tussi-Organidin NR:
    - Store at room temperature (between 59 to 86 degrees F)
    Tusso-C:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Virtussin AC:
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the use of the codeine; guaifenesin combination products for the relief of cough. Clinicians may wish to consult the individual monographs for more information about the specific contraindications and precautions for each agent.

    Asthma, bronchitis, chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, emphysema, fever, headache, respiratory depression, tobacco smoking

    Avoid coadministration with other CNS depressants, including alcohol; this combination increases the risk for respiratory depression, low blood pressure, and death. Additionally, codeine; guaifenesin combination products should not be used for persistent or chronic cough such as occurs with tobacco smoking, asthma, chronic obstructive pulmonary disease (COPD), emphysema, or chronic bronchitis or any other condition where cough is associated with excessive secretions, unless under the supervision of a health care professional. Indiscriminate use in these patients may precipitate respiratory insufficiency from suppression of the cough reflex. A recurrent or persistent cough (lasting for more than one week), or a cough accompanied by fever, nausea/vomiting, rash, or persistent headache may be signs of a more serious condition and should be evaluated by a physician.

    Labor, neonates, obstetric delivery, pregnancy

    Codeine; guaifenesin is classified in FDA pregnancy risk category C. No well-controlled studies in pregnant women have been performed. The pregnancy risk factor increases to FDA category D if codeine; guaifenesin is used for prolonged periods during pregnancy or in high doses close to term. Neonates whose mothers have been taking codeine; guaifenesin chronically may show some respiratory depression and/or withdrawal symptoms at birth or within a few days. Since the risk of respiratory depression increases with dose and proximity to labor and obstetric delivery, mothers anticipating the delivery of a premature infant should avoid using codeine; guaifenesin. Monitor infants born to mothers receiving narcotic analgesics closely for signs of respiratory depression.

    Hepatic disease

    Since codeine is metabolized in the liver, the combination of codeine; guaifenesin should be used cautiously in patients with hepatic disease. Codeine may accumulate leading to a prolonged duration of action and increased risk of toxicity in these patients. It may be appropriate to use a lower dose of codeine, but specific recommendations are not available.

    Renal failure, renal impairment

    The elimination of codeine is reduced in the presence of renal impairment or renal failure. Dose adjustments are required in patients with CrCl < 50 ml/min. Patients may be at risk of drug accumulation and associated toxicity if dose reductions are not implemented.

    Driving or operating machinery

    Codeine; guaifenesin combinations may cause dizziness, confusion or drowsiness, particularly if other CNS depressants are being used. Patients should be cautioned regarding driving or operating machinery until they know how this product will affect them.

    Abrupt discontinuation

    Short courses of codeine; guaifenesin for antitussive effects do not usually require tapering at the end of therapy. Abrupt discontinuation of prolonged, high dose therapy can result in withdrawal symptoms. These patients should be gradually tapered off codeine; guaifenesin to avoid a withdrawal reaction. Generally, a 50% decrease every 1—2 days of the daily codeine; guaifenesin dose will prevent withdrawal symptoms in patients who have been receiving large daily doses of codeine.

    Opiate agonist hypersensitivity

    Although true opiate agonist hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to codeine should not receive codeine; guaifenesin or other opioid agonists of the phenanthrene subclass including morphine, oxycodone and hydromorphone.

    Cardiac arrhythmias, cardiac disease, heart failure, hypovolemia, orthostatic hypotension

    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. Codeine; guaifenesin should be used with caution in patients with cardiac arrhythmias, hypotension, or hypovolemia. Guaifenesin should not be used for a cough that is specifically associated with heart failure or ACE inhibitor therapy.

    Children, infants, pulmonary disease, respiratory infection, respiratory insufficiency, sleep apnea

    The American Academy of Pediatrics (AAP) recommends against the use of codeine and codeine-containing products in neonates, infants, children, and adolescents for any indication, and multiple regulatory agencies provide guidance and/or restrictions on its use in clinical practice. 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. Patients with respiratory conditions (e.g., obstructive sleep apnea, asthma, respiratory infection, pulmonary disease, respiratory insufficiency) are particularly at increased risk for serious respiratory depression; deaths have occurred in children with obstructive sleep apnea who received codeine after tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine. If codeine-containing products are used in pediatric patients, respiratory status must be monitored closely. Codeine; guaifenesin should be dosed as needed (not scheduled around the clock) at the lowest effective dose for the shortest duration possible. Instruct parents and caregivers to stop use of codeine; guaifenesin and seek immediate medical attention if signs of overdose (slow or shallow breathing, difficult or noisy breathing, unusual sleepiness, or confusion) are observed. In reported cases, signs of morphine toxicity developed within 1 to 2 days after beginning codeine.

    Bladder obstruction, prostatic hypertrophy, urethral stricture, urinary retention

    Codeine can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients with bladder obstruction, pelvic tumors, urethral stricture, or men with prostatic hypertrophy may be more at risk for urinary retention.

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

    Codeine; guaifenesin should be used cautiously in patients with GI disease including GI obstruction, ulcerative colitis, or pre-existing constipation due to the effects of codeine on the gastrointestinal tract. Codeine should not be used in patients who have or are suspected of having paralytic ileus. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Patients with acute ulcerative colitis or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Opiate agonists are contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea. If possible, opiate agonists should not be given until the toxic substance has been eliminated.

    Breast-feeding

    It is not known if guaifenesin is excreted into breast milk, but codeine is distributed into breast milk in varying degrees depending upon the dose. Codeine is metabolized to morphine, which is also distributed into breast milk. Breast-fed infants 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 for episiotomy pain, 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 infant. 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. According to the manufacturer, because of the risk of adverse effects in the infant, a decision whether to discontinue breast-feeding the infant or to discontinue codeine; guaifenesin should be made. Although data in breast-feeding women are not available, some experts state that the maternal use of usual doses of dextromethorphan and guaifenesin is unlikely to be harmful to a nursing infant ; therefore, dextromethorphan; guaifenesin may represent a reasonable alternative in some patients. However, care should be taken to avoid preparations with a high alcohol content.

    Substance abuse

    Because codeine is an opiate agonist, codeine and guaifenesin combination products are 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 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. Codeine; guaifenesin is not approved for the management of substance abuse.

    Head trauma, increased intracranial pressure

    Patients with head trauma or with increased intracranial pressure should be given codeine; guaifenesin 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.

    Surgery

    As with all cough suppressants, codeine; guaifenesin should be used cautiously in patients who have undergone surgery, particularly thoracotomy or laparotomy. Suppression of the cough reflex may lead to retention of secretions postoperatively.

    Geriatric

    The geriatric or debilitated patient is more likely to be sensitive to the CNS and respiratory depressant effects of codeine. Dose selection for geriatric patients should be made with caution, usually starting at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function, and of co-morbidities or other drug therapies. 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.

    ADVERSE REACTIONS

    Severe

    toxic megacolon / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    seizures / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    bradycardia / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 15.0-90.0
    urinary retention / Early / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    respiratory depression / Rapid / Incidence not known
    euphoria / Early / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known
    dysphoria / Early / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known

    Mild

    drowsiness / Early / 24.0-50.0
    nausea / Early / 15.0-41.0
    vomiting / Early / 7.0-24.0
    dizziness / Early / 14.0-14.0
    miosis / Early / 0-10.0
    abdominal pain / Early / 5.0-5.0
    headache / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Hydrocodone: 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: 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: 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: 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: 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. Particular caution should be paid to combination with oxycodone. Aldesleukin, IL-2, is a CYP3A4 inhibitor, and the drug may increase oxycodone plasma concentrations and increase or prolong related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patient for an extended period of time and adjust oxycodone dosage as necessary.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aliskiren; Hydrochlorothiazide, HCTZ: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Alosetron: 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: 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: Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than 7 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: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Amiloride; Hydrochlorothiazide, HCTZ: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amiodarone: 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: 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: 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. 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amoxapine: 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: 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 inhibtion 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Amoxicillin; Clarithromycin; Omeprazole: 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 inhibtion 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Amprenavir: 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: 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.
    Anticholinergics: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Apomorphine: Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Apraclonidine: No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists.
    Aprepitant, Fosaprepitant: 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.
    Artemether; Lumefantrine: 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: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Asenapine: 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; Carisoprodol: 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.
    Aspirin, ASA; Carisoprodol; Codeine: 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.
    Aspirin, ASA; Oxycodone: 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.
    Atazanavir: 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: 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. 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Atracurium: 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; Difenoxin: 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: 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.
    Azelastine: 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: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Azole antifungals: 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 inhibtion 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. 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Baclofen: 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.
    Benazepril; Hydrochlorothiazide, HCTZ: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Bendroflumethiazide; Nadolol: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Benzonatate: The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Bethanechol: 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: 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: Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bisoprolol; Hydrochlorothiazide, HCTZ: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Brexpiprazole: Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including opiate agonists.
    Brimonidine: 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: 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: 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: 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: 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: 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: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Bupivacaine: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Bupivacaine; Lidocaine: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Buprenorphine: 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: 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. 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: 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: 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. 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: 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.
    Butorphanol: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Capsaicin; Metaxalone: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Carbamazepine: 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.
    Carbetapentane; Chlorpheniramine: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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.
    Cetirizine: Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Cetirizine; Pseudoephedrine: Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Chlordiazepoxide: 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: 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: 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.
    Chloroquine: The activity of codeine is due to its conversion to morphine via the cytochrome P450 2D6 hepatic isoenzyme. Chloroquine inhibits CYP2D6 and may theoretically decrease the conversion of codeine to morphine.
    Chlorothiazide: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: 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: 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: 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: 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: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorthalidone; Clonidine: Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists. Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorzoxazone: 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.
    Cimetidine: 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: 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: 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: 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: 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 inhibtion 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Clobazam: 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: 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: 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: Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Clorazepate: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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. 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: 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: 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: Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desipramine: 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: 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: 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: 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.
    Dexmedetomidine: Co-administration of dexmedetomidine with opiate agonists likely to lead to an enhancement of CNS depression.
    Dexpanthenol: 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: 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: 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.
    Diphenhydramine; Hydrocodone; Phenylephrine: 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: 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: 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: 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: 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.
    Elbasvir; Grazoprevir: 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: Eltrombopag is a UDP-glucuronyltransferase inhibitor. Opiate agonists are substrates of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of morphine is possible. Monitor patients for morphine-related adverse reactions if these drugs are coadministered.
    Eluxadoline: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Enflurane: 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: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Erythromycin: 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 inhibtion 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Erythromycin; Sulfisoxazole: 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 inhibtion 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Escitalopram: 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: 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: 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: 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.
    Ethotoin: Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
    Etomidate: Concomitant use of CNS depressants can potentiate the effects of codeine, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses.
    Flibanserin: 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: 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 inhibtion 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. 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Fluoxetine: 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: Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression, including opiate agonists. 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: 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: 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: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Fosphenytoin: 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: 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: 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: 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: 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: Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as opiate agonists, when administered concomitantly.
    Guanfacine: Central-acting adrenergic agonists like guanfacine have CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Haloperidol: Haloperidol inhibits CYP2D6 and may decrease the conversion of codeine to morphine, decreasing its effectiveness.
    Halothane: 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: 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.
    Hydralazine; Hydrochlorothiazide, HCTZ: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Irbesartan: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Lisinopril: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Losartan: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Methyldopa: Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly. Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Metoprolol: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Moexipril: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Olmesartan: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Propranolol: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Quinapril: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Spironolactone: Opiate agonists like codeine may potentiate orthostatic hypotension when given concomitantly with spironolactone. Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Telmisartan: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Triamterene: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrocodone: 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: 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: 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: 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: 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: 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: 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.
    Ibuprofen; Oxycodone: 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: 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: 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: 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: 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.
    Isocarboxazid: Concomitant use of codeine with central nervous system (CNS) depressants such as monoamine oxidase inhibitors (MAOIs) can potentiate the effects of codeine, possibly leading to respiratory or CNS depression, sedation, or hypotensive responses. The manufacturer of codeine recommends a 14-day washout period between the discontinuation of an MAOI and the initiation of codeine. If combination therapy is necessary, initiate with low dosages of the opiate followed by careful titration. Advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Isoflurane: 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; Pyrazinamide, PZA; Rifampin: 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: 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: 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 inhibtion 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. 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Ketamine: The use of ketamine with other CNS depressants, including opiate agonists, potentiate CNS depression and/or increase the risk of developing respiratory depression.
    Ketoconazole: 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 inhibtion 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. 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Lactobacillus: 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.
    Levobupivacaine: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Levocetirizine: Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Lidocaine: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Lincosamides: 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.
    Loperamide: 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: 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: 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: 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: 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: 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: 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: 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: 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 Salts: 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: 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: 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.
    Mepivacaine: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Mepivacaine; Levonordefrin: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Meprobamate: 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: 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: 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: 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.
    Methocarbamol: 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.
    Methyclothiazide: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Methyldopa: Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly.
    Metoclopramide: Opiate agonists antagonize GI motility and can decrease the GI motility enhancing effects of metoclopramide. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as metoclopramide, may result in a reduction in the analgesic effect of hydrocodone.
    Metolazone: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Metyrapone: 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: The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
    Midazolam: 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: 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.
    Mirabegron: 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: 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: 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.
    Mivacurium: 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: 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: Concomitant use of codeine with central nervous system (CNS) depressants such as monoamine oxidase inhibitors (MAOIs) can potentiate the effects of codeine, possibly leading to respiratory or CNS depression, sedation, or hypotensive responses. The manufacturer of codeine recommends a 14-day washout period between the discontinuation of an MAOI and the initiation of codeine. If combination therapy is necessary, initiate with low dosages of the opiate followed by careful titration. Advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Morphine: 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: 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: 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: 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: 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: 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: 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: 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: The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
    Neuromuscular blockers: 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: 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: 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: 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: 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: 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: 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.
    Oritavancin: 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: 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.
    Oxazepam: 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.
    Oxycodone: 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: 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.
    Paliperidone: 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: 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: 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: 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: 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: 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: 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: 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. 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.
    Perampanel: 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: 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: 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. 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: Concomitant use of codeine with central nervous system (CNS) depressants such as monoamine oxidase inhibitors (MAOIs) can potentiate the effects of codeine, possibly leading to respiratory or CNS depression, sedation, or hypotensive responses. The manufacturer of codeine recommends a 14-day washout period between the discontinuation of an MAOI and the initiation of codeine. If combination therapy is necessary, initiate with low dosages of the opiate followed by careful titration. Advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Phenothiazines: 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: 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: 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.
    Posaconazole: 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 inhibtion 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. 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Pramipexole: The use of opiate agonists in combination with pramipexole may increase the risk of clinically significant sedation via a pharmacodynamic interaction.
    Pramlintide: 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.
    Pregabalin: 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: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Prilocaine; Epinephrine: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Procarbazine: Opiate agonists may cause additive sedation or other CNS effects when given in combination with procarbazine.
    Prochlorperazine: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Opiate agonists (e.g., alfentanil, codeine, hydrocodone, morphine, sufentanil, etc.) may cause additive CNS depression, drowsiness, dizziness or hypotension, so use with MAOIs should be cautious; lower initial dosages of the opiate are recommended followed by careful titration.
    Rifampin: 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: 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: 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: 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: 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: 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: Due to the CNS depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Saquinavir: 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.
    Sedating H1-blockers: 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, Transdermal: Concomitant use of codeine with central nervous system (CNS) depressants such as monoamine oxidase inhibitors (MAOIs) can potentiate the effects of codeine, possibly leading to respiratory or CNS depression, sedation, or hypotensive responses. The manufacturer of codeine recommends a 14-day washout period between the discontinuation of an MAOI and the initiation of codeine. If combination therapy is necessary, initiate with low dosages of the opiate followed by careful titration. Advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Selegiline: Concomitant use of codeine with central nervous system (CNS) depressants such as monoamine oxidase inhibitors (MAOIs) can potentiate the effects of codeine, possibly leading to respiratory or CNS depression, sedation, or hypotensive responses. The manufacturer of codeine recommends a 14-day washout period between the discontinuation of an MAOI and the initiation of codeine. If combination therapy is necessary, initiate with low dosages of the opiate followed by careful titration. Advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Sertraline: The activity of codeine is due to its conversion to morphine via the cytochrome P450 CYP2D6 hepatic isoenzyme. The analgesic activity of codeinemay be reduced when it is combined with drugs that inhibit CYP2D6, such as sertraline.
    Sevoflurane: 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: 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: 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 Oxybate: Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with opiate agonists.
    Solifenacin: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use.
    Spironolactone: Opiate agonists like codeine may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Succinylcholine: 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.
    Suvorexant: 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: 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.
    Temazepam: 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: 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: 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: 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: 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: Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Thiethylperazine: 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.
    Thioridazine: 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: 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: 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 inhibtion 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. 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Tipranavir: 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: 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.
    Tolcapone: 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may been seen. 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. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Pharmacology texts report that meperidine exerts less pronounced effects on GI smooth muscle than other opiate agonists.
    Tramadol: 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: Concomitant use of codeine with central nervous system (CNS) depressants such as monoamine oxidase inhibitors (MAOIs) can potentiate the effects of codeine, possibly leading to respiratory or CNS depression, sedation, or hypotensive responses. The manufacturer of codeine recommends a 14-day washout period between the discontinuation of an MAOI and the initiation of codeine. If combination therapy is necessary, initiate with low dosages of the opiate followed by careful titration. Advise patients against driving or performing other hazardous activities until they know how the combination affects them.
    Trazodone: 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: 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: 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: 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: 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.
    Trimipramine: 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: Opiate agonists should be used cautiously with antimuscarinics since additive depressive effects on GI motility or bladder function may be seen.
    Tubocurarine: 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: 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: 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.
    Vigabatrin: 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: 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: 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 inhibtion 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. 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, particuarly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Zaleplon: 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: Concurrent use of ziconotide and opiate agonists may result in an increased incidence of dizziness and confusion.
    Ziprasidone: 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.
    Zolpidem: 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

    It is not known if guaifenesin is excreted into breast milk, but codeine is distributed into breast milk in varying degrees depending upon the dose. Codeine is metabolized to morphine, which is also distributed into breast milk. Breast-fed infants 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 for episiotomy pain, 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 infant. 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. According to the manufacturer, because of the risk of adverse effects in the infant, a decision whether to discontinue breast-feeding the infant or to discontinue codeine; guaifenesin should be made. Although data in breast-feeding women are not available, some experts state that the maternal use of usual doses of dextromethorphan and guaifenesin is unlikely to be harmful to a nursing infant ; therefore, dextromethorphan; guaifenesin may represent a reasonable alternative in some patients. However, care should be taken to avoid preparations with a high alcohol content.

    MECHANISM OF ACTION

    The cumulative actions of codeine in combination with guaifenesin result in the relief of cough and associated symptoms.
    •Codeine: The antitussive effects of codeine are mediated through direct action on receptors in the cough center of the medulla in the brain. Codeine also has a drying effect on the respiratory tract and increases the viscosity of bronchial secretions. Cough suppression can be achieved at lower doses than those required to produce analgesia.
    •Guaifenesin: Guaifenesin is an expectorant which increases the output of phlegm (sputum) and bronchial secretions by reducing adhesiveness and surface tension. The increased flow of less viscous secretions promotes ciliary action and changes a dry, unproductive cough to one that is more productive and less frequent. By reducing the viscosity and adhesiveness of secretions, guaifenesin increases the efficacy of the mucociliary mechanism in removing accumulated secretions from the upper and lower airway. The expectorant effect can reduce cough frequency. Guaifenesin can also be beneficial for irritating, nonproductive coughs and for conditions in which thick mucous secretions are produced.

    PHARMACOKINETICS

    Codeine; guaifenesin combinations are administered orally as a syrup, solution or tablet.
     
    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. Elimination half-life ranges from 3—4 hours for codeine and is 2 hours for morphine. Elimination occurs renally as the unchanged drug, norcodeine, and free and conjugated morphine. Negligible amounts are excreted in the feces.
    Guaifenesin: Guaifenesin is rapidly hydrolyzed (60% within seven hours) and then excreted in the urine, with beta-(2-methoxyphenoxy)-lactic acid as its major urinary metabolite. Excessive use of guaifenesin may result in urolithiasis; renal stones have been documented to contain beta-(2-methoxyphenoxy)-lactic acid and other guaifenesin metabolites. Additional pharmacokinetic information is not known.

    Oral Route

    Codeine: Codeine is well absorbed after oral administration. Peak antitussive activity is achieved within 1—2 hours of oral administration and can last for 4—6 hours. Protein binding is negligible.
    Guaifenesin: Guaifenesin is rapidly absorbed from the GI tract and has a plasma half-life of about 1 hour. No unchanged drug could be detected in the urine following administration of oral guaifenesin.