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  • CLASSES

    Opiate Anesthetics
    Opioid Agonists

    BOXED WARNING

    Alcoholism, depression, substance abuse

    Fentanyl is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Addiction may occur in patients who obtain fentanyl illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. To discourage abuse, the smallest appropriate quantity of fentanyl needed for appropriate analgesia should be prescribed, and appropriate disposal instructions for unused drug should be given to patients.

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

    Fentanyl transdermal patches and the iontophoretic transdermal system are contraindicated for use in patients with significant respiratory depression or compromise especially in the absence of monitoring and resuscitative equipment, and/or acute or severe bronchial asthma (e.g., status asthmaticus). Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Use appropriate caution when considering opioid therapy in both opioid naive and opioid-tolerant patients with respiratory depression and severe pulmonary disease. Receipt of moderate fentanyl doses in these patients may significantly decrease pulmonary ventilation. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. The long-acting transdermal patches should be reserved for opioid-tolerant patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Do not use as a "prn" or "as needed" analgesic, for acute pain, or if the pain is mild or not expected to persist for an extended period of time. Only patients who are tolerant to around-the-clock opioids should receive transmucosal immediate release products, as non-tolerant patients may experience potentially life-threatening respiratory depression at any dose. Proper dosing and titration are essential; patients should be monitored for respiratory depression, particularly during the first 24 to 72 hours after therapy initiation or a dose increase. When using fentanyl transdermal patches, note the risk of life-threatening respiratory depression is greatest during the first 2 applications following treatment initiation or a dose increase. The risk of respiratory depression persists beyond patch removal due to continued drug absorption; monitor patients for 24 to 72 hours following discontinuation. Caution should be exercised when converting from a different opioid to fentanyl, as initial dose overestimation may lead to fatal overdose in opioid-tolerant patients. In patients with pulmonary disease such as chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to fentanyl, as even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, sleep apnea, or obesity, as obesity is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Careful monitoring is required, particularly when CYP450 3A4 inhibitors or inducers are used concomitantly; concurrent use of a 3A4 inhibitor or discontinuation of a concurrently used 3A4 inducer may increase plasma fentanyl concentrations and potentiate the risk of fatal respiratory depression. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. A high level of vigilant monitoring is recommended and supportive care should be given as needed.

    Potential for overdose or poisoning, requires a specialized care setting, requires an experienced clinician

    Like all opioid analgesics, fentanyl is associated with significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Fentanyl products are not interchangeable and conservative conversion from other opioids to fentanyl is recommended; inappropriate conversion from another opioid agonist or mcg for mcg substitution of one fentanyl product for another may result in fatal overdose with the first dose. Significant pharmacokinetic differences exist between products. Further, the various dosage forms and products are indication specific by design. Transdermal patches should be reserved for management of chronic, severe pain in opioid-tolerants patients who require continuous, around-the-clock, opioid analgesia for an extended period of time. Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys are indicated only for the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Therapy requires an experienced clinician to manage the complex and product-specific treatment. For example, Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys are intended to be prescribed only by oncologists and pain specialists who are knowledgeable of and skilled in the use of schedule II opioids to treat cancer pain. Due to increased fentanyl exposure, increased monitoring is warranted in patients with Grade 1 mucositis receiving the sublingual spray (Subsys). The sublingual spray should be avoided in patients with Grade 2 mucositis unless the benefits outweigh the potential risk of increased respiratory depression. As of December 2011, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program to obtain transmucosal products, which include Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys. The TIRF REMS is designed to reduce the risks of abuse, misuse, addiction, and overdose of TIRF medications. Patient and prescriber enrollment is not necessary for inpatient administration (e.g., hospitals, hospices, and long-term care facilities). Likewise, only healthcare professionals who are knowledgeable of the use of opioids for the management of chronic pain should prescribe Duragesic. The Ionsys iontophoretic transdermal system is only available through a restricted program called the Ionsys REMS Program due to the potential for life-threatening respiratory depression from accidental exposure. Ionsys must only be used in the inpatient setting and discontinued before the patient leaves the hospital. Patients should be under medical supervision by healthcare professionals knowledgeable in the use of potent opioids for pain treatment and in the detection and management of hypoventilation. Intravenous fentanyl should only be administered by health care professionals trained in anesthesiology who are familiar with the respiratory effects of potent opioids. In addition, use of anesthetic doses of IV fentanyl requires a specialized care setting where an opiate antagonist, oxygen, and controlled respiration facilities are present.

    Accidental exposure

    Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home, either full time or visiting, and counsel them regarding the dangers to children from accidental exposure. Sublingual/transmucosal products (Abstral, Actiq, Fentora, Onsolis, Subsys), nasal spray (Lazanda), transdermal patches (Duragesic), and the iontophoretic transdermal system (Ionsys) contain fentanyl in an amount that can be fatal to a child, pet, or opioid-naive adult. Advise patients and caregivers to wash hands after handling any fentanyl product or packaging and to seek immediate medical help if an accidental exposure occurs. Contact with unwashed or unclothed application sites from the transdermal patch can result in secondary exposure and should be avoided; examples include transfer of the drug to a child's body while hugging, sharing the same bed as the patient, or accidentally sitting on a patch. Keep both used and unused dosage units out of the reach of children or pets. In the event that an Abstral, Actiq, Fentora, Onsolis, Subsys unit is not completely consumed or is not longer needed, it must be properly disposed of as soon as possible. Used patches still may contain enough fentanyl to cause a fatal overdose in a child, adult, or pet. Proper disposal out of the reach or children or pets is essential. Placing a patch in the mouth, chewing it, or swallowing it may cause choking or overdose that may be fatal. Dispose of the fentanyl patch by folding the adhesive side of the patch to itself, then flush the patch down the toilet. Dispose of Abstral, Actiq, Fentora, Onsolis by flushing the medication down the toilet; do not flush foil packages or cartons. Discard fentanyl from Lazanda nasal spray and Subsys sublingual spray according to manufacturer instructions. Also, do not use a patch that is leaking or damaged in any way. Direct exposure to the adhesive gel in patches or to the iontophoretic transdermal system or its hydrogel components may lead to serious adverse events such as respiratory depression and fatal overdose. If accidental skin contact occurs, thoroughly rinse exposed skin with large amounts of water; do not use soap, alcohol, or other solvents to remove the gel because they may enhance the drug's ability to penetrate the skin. If the iontophoretic transdermal system is not handled with gloves by healthcare professionals, accidental overdose may occur.

    Labor, neonatal opioid withdrawal syndrome, pregnancy

    Fentanyl is classified in FDA pregnancy category C; there have been no well-controlled studies performed in pregnant women. In animal studies, fentanyl use has resulted in inconsistent fertility and fetal effects without dose-dependent or species-dependent correlation. The drug readily crosses the placenta and should only be given to pregnant women if the potential benefit justifies the risk. Although IV and epidural fentanyl are commonly used in labor or obstetric delivery , the manufacturers do not recommend such use citing insufficient data. Infants and neonates are especially sensitive to respiratory depression, so appropriate precautions should be taken if fentanyl is used during labor. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. The risk of respiratory and CNS depression is especially important for premature infants who are particularly sensitive. A specific opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate. Further, the prolonged maternal use of long-acting opioids, such as fentanyl transdermal patches, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

    Ambient temperature increase, fever, heating pad, skin abrasion, sunlight (UV) exposure

    Application of transdermal patches to areas of preexisting skin abrasion can subject the patient to an additional risk of local adverse effects; patches are only for application to intact skin. Also, use only intact patches; use of damaged or cut patches can lead to a potentially fatal fentanyl dose due to rapid drug release. Serum concentrations of fentanyl could increase by approximately one-third in patients with fever > 104 degrees F (40 degrees C) due to temperature dependent increase in fentanyl release from the transdermal system and increased skin permeability. Patients with fever who are wearing fentanyl transdermal patches should be carefully monitored for increased side effects and dosage adjustments may be necessary. Patients should avoid strenuous exertion that may increase core body temperature. Application of heat over fentanyl transdermal patches worn by healthy adults increased fentanyl mean serum concentration (Cmax) by 61% and mean systemic exposure (AUC) by 120%. Fatal overdose attributable to heat exposure has occurred. Patients should be advised to avoid exposing the transdermal application site to direct external heat sources, such as a heating pad, electric blankets, heat lamps, saunas, hot tubs, heated water beds, hot baths, sunbathing (including tanning beds and other sunlight (UV) exposure), conditions of ambient temperature increase, etc.

    DEA CLASS

    Rx, schedule II

    DESCRIPTION

    Phenylpiperidine synthetic opiate agonist
    Used with general, regional, and spinal anesthesia; also for chronic and breakthrough pain
    Formulations not interchangeable on a mcg-to-mcg basis, even those administered via same route, due to significant pharmacokinetic differences

    COMMON BRAND NAMES

    ABSTRAL, Actiq, Duragesic, Fentora, IONSYS, Lazanda, Sublimaze, SUBSYS

    HOW SUPPLIED

    ABSTRAL/Fentora Sublingual Tablet, SL: 100mcg, 200mcg, 300mcg, 400mcg, 600mcg, 800mcg
    Actiq/Fentanyl Citrate Buccal Lozenge: 200mcg, 400mcg, 600mcg, 800mcg, 1200mcg, 1600mcg
    Actiq/Fentanyl Citrate Transmucosal Lozenge: 200mcg, 400mcg, 600mcg, 800mcg, 1200mcg, 1600mcg
    Duragesic/Fentanyl Transdermal Film ER: 1h, 12mcg, 25mcg, 37.5mcg, 50mcg, 62.5mcg, 75mcg, 87.5mcg, 100mcg
    Fentanyl Citrate/Sublimaze Intramuscular Inj Sol: 1mL, 50mcg
    Fentanyl Citrate/Sublimaze Intravenous Inj Sol: 1mL, 50mcg
    Fentora Buccal Tablet, SL: 100mcg, 200mcg, 400mcg, 600mcg, 800mcg
    Fentora Transmucosal Tablet, SL: 100mcg, 200mcg, 400mcg, 600mcg, 800mcg
    IONSYS Transdermal Patch, Electrically Controlled: 1actuation, 40mcg
    Lazanda Nasal Spray Met: 1actuation, 100mcg, 300mcg, 400mcg
    Lazanda Transmucosal Spray Met: 1actuation, 100mcg, 300mcg, 400mcg
    SUBSYS Sublingual Spray Met: 1actuation, 100mcg, 200mcg, 400mcg, 600mcg, 800mcg

    DOSAGE & INDICATIONS

    For the control of moderate pain or severe pain.
    For intraoperative or procedural management of severe pain, for use only in a monitored anesthesia care setting in the hospital.
    Intravenous or Intramuscular dosage
    Adults

    50 to 100 mcg IM, or by slow IV over 1 to 2 minutes, given 30 to 60 minutes before surgery.

    For control of postoperative pain in the recovery room.
    Intravenous or Intramuscular dosage
    Adults

    50 to 100 mcg IM or slow IV over 1 to 2 minutes for the control of pain, tachypnea, and/or delirium. The dose may be repeated in 1 to 2 hours, as needed.

    Children† and Adolescents† 2 years and older

    0.5 to 2 mcg/kg/dose IV or IM every 1 to 2 hours as needed for pain relief. Max initial dose: 50 mcg. In general, young children require higher doses (e.g., 2 to 3 mcg/kg/dose) than older children and adolescents. Titrate dosage as needed to achieve adequate pain relief.

    Infants† and Children† through 1 year of age

    0.5 to 2 mcg/kg/dose IV or IM every 1 to 2 hours as needed for pain relief. In general, young children require higher doses (e.g., 2 to 3 mcg/kg/dose) than infants and older children. Titrate dosage as needed to achieve adequate pain relief.

    Neonates†

    0.5 to 3 mcg/kg/dose IV every 2 to 4 hours as needed. Titrate dosage as needed to achieve adequate pain relief.

    Epidural dosage†
    Adults

    Not FDA-approved for epidural use in U.S. but commonly used clinically. Initial bolus doses range 10 mcg to 100 mcg, depending on clinical condition for use. Typical fentanyl continuous epidural rate range for post-surgical pain control: 0.5 to 1 mcg/kg/hour epidurally. Standard epidural concentrations and dose regimens may vary with condition for use. Patients often receive concomitant epidural bupivacaine at concentrations of 0.0625% or 0.075%. Fentanyl has also been used in patient controlled epidural analgesia protocols (PCEA), with varied dosing regimens depending on the setting of use and if bupivacaine or ropivacaine are used concurrently in the epidural regimen. Use preservative-free solutions.

    For the management of chronic severe pain in opioid-tolerant patients who require daily, around-the-clock, long-term opioid treatment.
    Transdermal dosage (Duragesic)
    Adults

    TO CONVERT OPIOID-TOLERANT ADULT PATIENTS FROM OTHER OPIATE AGONISTS TO FENTANYL TRANSDERMAL 72-HOUR SYSTEM: 1) Calculate the previous 24-hour opioid analgesic requirement; 2) Convert this amount to the equianalgesic oral morphine dose; 3) follow the FDA-approved conversion chart in the product label to convert 24-hour oral morphine equivalents dose to the corresponding transdermal fentanyl system dose. Initially, apply at minimum a 25 mcg/hour transdermal patch for patients receiving at least 60 mg/day oral morphine equivalents. Discontinue all other around-the-clock opioid drugs upon transdermal fentanyl initiation. 4) Change patch system every 72 hours. DOSE TITRATION: If adequate analgesia is not achieved, may titrate the initial dosage upward after 3 days (72 hours); subsequent titrations should be made no more frequently than every 6 days. Use short-acting opioid agonists as needed for 24 hours after initial application; breakthrough pain may require supplemental doses even after a transdermal dose is established. Appropriate transdermal system dosage adjustments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/day of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage. The patch should be changed every 72 hours; however, some patients may require patch application at 48-hour intervals to maintain adequate analgesia. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. DISCONTINUATION: To convert to another opioid, remove the fentanyl transdermal system and titrate the dose of the new analgesic to adequate pain relief. Once the patch is removed, 17 hours or more are required for a 50% decrease in fentanyl concentrations. To discontinue the transdermal system when not converting to another opioid, gradually decrease the system dose by 50% every 6 days. Monitor patients for withdrawal symptoms, as these are possible with dose conversion or adjustment. Transdermal fentanyl should be reserved for patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would otherwise provide inadequate pain management. Opioid-tolerant adult patients are defined as those taking, for a minimum of 1 week, at least 60 mg/day oral morphine, 30 mg/day oral oxycodone, 8 mg/day oral hydromorphone, or an equivalent dose of another opioid.

    Children and Adolescents 2 years and older

    TO CONVERT OPIOID-TOLERANT PEDIATRIC PATIENTS FROM OTHER OPIATE AGONISTS TO FENTANYL TRANSDERMAL 72-HOUR SYSTEM: 1) Calculate the previous 24-hour opioid analgesic requirement; 2) Convert this amount to the equianalgesic oral morphine dose; 3) follow the FDA-approved conversion chart in the product label to convert 24-hour oral morphine equivalents dose to the corresponding transdermal fentanyl system dose. Initially, apply at minimum a 25 mcg/hour transdermal patch for patients receiving at least 60 mg/day oral morphine equivalents. Discontinue all other around-the-clock opioid drugs upon transdermal fentanyl initiation. Some experts suggest opioid-tolerant pediatric patients receiving 30 mg/day or more of oral morphine equivalents can be safely initiated on the 12.5 mcg/hour transdermal system. Open-label trials have started opioid-tolerant pediatric patients receiving 45 mg/day of oral morphine equivalents on a fentanyl transdermal system of 25 mcg/hour with a low incidence of adverse respiratory events. 4) Change patch system every 72 hours. DOSE TITRATION: If adequate analgesia is not achieved, may titrate the initial dosage upward after 3 days (72 hours); subsequent titrations should be made no more frequently than every 6 days. Use short-acting opioid agonists as needed for 24 hours after initial application; breakthrough pain may require supplemental doses even after a transdermal dose is established. Appropriate transdermal system dosage adjustments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/day of oral morphine to a 12.5 mcg/hour increase in fentanyl dosage. Change patch system every 72 hours; dosing intervals less than this are not recommended in children and adolescents. Monitor patients frequently for respiratory depression, particularly during the first 24 to 72 hours after initiation or dose escalation. DISCONTINUATION: To convert to another opioid, remove the fentanyl transdermal system and titrate the dose of the new analgesic to adequate pain relief. Once the patch is removed, 17 hours or more are required for a 50% decrease in fentanyl concentrations. To discontinue the transdermal system when not converting to another opioid, gradually decrease the system dose by 50% every 6 days. Monitor patients for withdrawal symptoms, as these are possible with dose conversion or adjustment.

    For the management of severe breakthrough cancer pain in opioid-tolerant patients.
    Transmucosal dosage (e.g., Actiq oral lozenge or generic equivalents ONLY)
    Adults and Adolescents 16 years and older

    Initially, a single 200-mcg lozenge (Actiq) placed between the cheek and lower gum as needed for breakthrough pain. The unit should be sucked, not chewed, over a period of 15 minutes. If pain is not relieved within 15 minutes after complete consumption, may repeat dose once. Max: 2 lozenge units/breakthrough pain episode. Do not repeat additional dosing for at least 4 hours. Max: 4 lozenge units/day. An initial titration supply of only six 200-mcg lozenge units should be prescribed to limit the number of units in the home and decrease the potential for confusion and overdose. Patients/caregivers should only have 1 strength of lozenge available. TITRATION: If several consecutive breakthrough pain episodes require more than 1 unit for treatment, practitioners should increase the dose to the next available strength. Evaluate the new dose over 1 to 2 days to determine if adequate pain relief and acceptable side effects occur. Re-evaluate maintenance opioid therapy if the patient experiences more than 4 episodes/day of breakthrough pain once an appropriate breakthrough dose is determined. If respiratory depression or signs of excessive sedation occur before unit is completely consumed, immediately remove unit from the patient's mouth; subsequent doses should be decreased.

    Buccal or Sublingual dosage (Fentora buccal tablets ONLY)
    Adults

    Initially for a breakthrough pain episode, 100 mcg buccally (placed above a rear molar between the upper cheek and gum) until the buccal tablet has disintegrated. Patients must not suck, chew, or split the tablets. The patient may swallow any fragments that remain after 30 minutes. During an episode of breakthrough pain, one additional dose of the same strength, if needed, may be taken 30 minutes after the start of the previous administration, but no further doses may be used for the episode. At least 4 hours must elapse before treating the next breakthrough pain episode with Fentora. TITRATION: If treatment of several consecutive breakthrough pain episodes requires more than 1 dose/episode, increase the dose. For example, if more than 100 mcg is needed, place one 100 mcg tablet on each side of the mouth in the buccal cavity (total of two 100 mcg tablets). If this dose does not control the pain, place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate above 400 mcg/dose by 200 mcg increments. Once an effective dose has been achieved, use only one Fentora tablet of the correct dose strength per breakthrough pain episode and administer either via the buccal (between the upper cheek and gum above a rear molar) or sublingual (under the tongue) route. Once an appropriate breakthrough pain dose is determined, re-evaluate the maintenance (round-the-clock) opioid dose if there are more than 4 breakthrough pain episodes/day. SAFETY: To help prevent confusion and overdose, minimize the number of tablet strengths available to a patient at any time. Instruct patients to use all units of a particular strength before increasing to a higher dose. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.

    Transmucosal dosage (Onsolis oral dissolving film ONLY)
    Adults

    Initially, place a 200-mcg film on the inside of the cheek. Conversion instructions are not available for any other fentanyl product; always initiate at the 200-mcg dose regardless of previous breakthrough pain medication use. Titrate by 200 mcg in each subsequent episode until the dose provides adequate analgesia with tolerable side effects. Separate doses by at least 2 hours. Use only one dose per episode of breakthrough pain. During titration, multiple films may be placed on both sides of the mouth; do NOT overlap or stack films on top of each other. Do not use more than four 200-mcg films simultaneously. Doses of 1,200 mcg are achieved by using one 1,200 mcg film. Maximum: 1,200 mcg/dose and not to exceed 4 doses per day. Once an adequate dose for breakthrough pain episodes is determined, re-evaluate the dose of the maintenance (around-the-clock) opioid if a patient has greater than 4 breakthrough pain episodes per day. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those who are taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.

    Sublingual tablet dosage (Abstral ONLY)
    Adults

    Initially, 100 mcg sublingually until dissolved. Conversion instructions are not available for any other fentanyl product other than Actiq; therefore, except for patients already using Actiq, always initiate Abstral at the same dose (100 mcg) regardless of previous pain medication dosing. During an episode of breakthrough pain, 1 additional dose of the same strength, if needed, may be taken 30 minutes after the previous dose was given. Do not use more than 2 doses of Abstral per episode of breakthrough pain. At least 2 hours must elapse before treating another breakthrough pain episode. CONVERSION FROM ACTIQ: For patients on a current Actiq dose of 400 mcg or less, start Abstral at 100 mcg/dose and titrate using multiples of 100 mcg. For patients converting from an Actiq dose of 600 to 1200 mcg, start Abstral at 200 mcg/dose and titrate using multiples of 200 mcg. For patients converting from Actiq 1600 mcg, start Abstral 400 mcg/dose and titrate using multiples of 400 mcg. TITRATION: Titrate dose over consecutive episodes of breakthrough pain, as needed. In patients on a current Abstral dose of 100 to 300 mcg, titrate using multiples of 100 mcg. In patients on a current Abstral dose of 400 to 600 mcg, titrate using multiples of 200 mcg. Doses more than 800 mcg have not been studied. Do not exceed 4 sublingual tablets at a time. Do not treat more than 4 episodes of breakthrough pain in a day with Abstral. If a patient has greater than 4 breakthrough pain episodes per day once breakthrough pain dose is stable, re-evaluate the maintenance (around-the-clock) opioid dose. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those who are taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.

    Sublingual spray dosage (Subsys ONLY)
    Adults

    Initially, 100 mcg sprayed sublingually. Conversion instructions are not available for any other fentanyl product other than Actiq; therefore, except for patients already using Actiq, always initiate Subsys at the same dose (100 mcg) regardless of previous pain medication dosing. CONVERSION FROM ACTIQ: For patients converting from Actiq 400 mcg/dose or less, the initial dose is 100 mcg sprayed sublingually. For patients currently on Actiq 600 to 800 mcg per dose, the initial dose is 200 mcg sprayed sublingually. Patients previously using 1,200 to 1,600 mcg of Actiq should receive an initial dose of 400 mcg sprayed sublingually. TITRATION: During an episode of breakthrough pain, one additional dose of the same strength, if needed, may be taken 30 minutes after the previous dose. Do not use more than 2 doses of Subsys per episode of breakthrough pain. At least 4 hours must elapse before treating another breakthrough pain episode. Titrate the dose carefully in a stepwise manner, as needed, after a single administration of the current dose fails to adequately treat breakthrough pain during several consecutive episodes. Titration steps are 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,200 mcg, then 1,600 mcg per dose. To avoid overdose during titration, patients should have only 1 sublingual spray strength available at any time. Once titrated to an adequate dose, patients should use only one Subsys dose of the appropriate strength per breakthrough pain episode. Do not treat more than 4 episodes of breakthrough pain in a day. Once an appropriate breakthrough dose is determined, if a patient has greater than 4 breakthrough pain episodes per day, then re-evaluate the maintenance (around-the-clock) opioid dose. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those who are taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.

    Intranasal dosage (Lazanda)
    Adults

    Initially, 1 spray (100 mcg/spray) intranasally in 1 nostril. Always initiate with a 100 mcg dose, regardless of previous pain medication dosing. If adequate analgesia is obtained within 30 minutes of administration, continue to treat subsequent episodes of breakthrough pain with this dose. At least 2 hours must elapse before another dose. If adequate analgesia is not obtained within 30 minutes of administration, may titrate at consecutive episodes of breakthrough pain. During any episode of breakthrough cancer pain, if there is inadequate pain relief after 30 minutes following Lazanda administration, or if a separate episode of breakthrough cancer pain occurs before the next dose is permitted (i.e. within 2 hours), the patients may use a rescue medication as directed by their healthcare provider. TITRATION: Titrate if needed to find a dose that provides adequate analgesia with tolerable side effects. At least 2 hours must elapse between each dose. First increase to 200 mcg/dose (1 spray of 100 mcg/spray in each nostril). If needed, subsequent titration to 400 mcg/dose (1 spray of 400 mcg/spray in 1 nostril), 600 mcg/dose (1 spray of 300 mcg/spray in each nostril), and then 800 mcg/dose (1 spray of 400 mcg/spray in each nostril) may be used. Maximum: 800 mcg/dose per breakthrough pain episode. Treat a maximum of 4 episodes or less daily with this medication. Once an appropriate breakthrough pain dose is determined, re-evaluate the maintenance (round-the-clock) opioid dose if there are more than 4 breakthrough pain episodes/day. USE FOR OPIOID TOLERANT PATIENTS ONLY: Patients considered opioid tolerant are those taking for 1 week or longer opiates equivalent to at least: 60 mg/day PO morphine, 25 mcg/hour of transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, or 25 mg/day PO oxymorphone.

    For short-term management of acute postoperative pain in the hospital setting using a fentanyl iontophoretic transdermal system (ITS) for patient-controlled analgesia.
    Transdermal dosage (Ionsys iontophoretic transdermal system only)
    Adults

    Use only after patients have been titrated to an acceptable level of analgesia using other opioid analgesics. One dose activation delivers 40 mcg transdermally over 10 minutes. Instruct patients on how to self-operate the system; patients should self-administer doses. Apply only 1 system at a time. A maximum of six 40-mcg doses may be administered per hour. Each system operates up to 24 hours or 80 doses, whichever comes first. Each subsequent system is applied to a different skin site. Maximum total duration of treatment should not exceed 3 days (72 hours). If inadequate analgesia occurs, provide breakthrough pain medication or replace with an alternate analgesic medication. If conversion to alternate analgesic is needed upon discontinuation of the system, titrate the dose of the new analgesic until adequate analgesia is obtained, considering that serum fentanyl concentrations will gradually decrease upon system removal.

    For adjuvant management of general anesthesia maintenance and intraoperative pain control.
    For minor surgical procedures and for use in the immediate postoperative period.
    Intravenous or Intramuscular dosage
    Adults

    2 mcg/kg IV or IM. Maintenance doses are infrequently needed.

    Adolescents

    2 mcg/kg IV or IM as a total "low" dose for induction and maintenance.

    Children 2 to 12 years

    2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance. In general, young children require higher doses than older children and adolescents.

    Neonates†, Infants†, and Children 1 year of age†

    Limited data available. 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance, based on recommended doses in children 2 to 12 years of age. In general, young children require higher doses than neonates and infants.

    For major surgery, providing analgesia and some relief from the stress response.
    NOTE: Respiratory depression at this dosage level requires artificial ventilation.
    Intramuscular or Intravenous dosage
    Adults

    2 to 20 mcg/kg IM or by slow IV. Additional doses may be required for maintenance if lightening of anesthesia or surgical stress becomes evident. Respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.

    Adolescents

    2 to 20 mcg/kg IV or IM as a total "moderate" dose for induction and maintenance. Respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.

    Children 2 to 12 years

    2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance per the manufacturer. Larger weight-based dosing recommendations are discussed for a "moderate dose" (2 to 20 mcg/kg total dose) range, but may be excessive in this population. In general, young children require higher doses than older children and adolescents. With "moderate" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.

    Neonates†, Infants†, and Children 1 year of age†

    Limited data available. 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient based on dosing in children 2 to 12 years of age for induction and maintenance. Larger weight-based dosing recommendations are discussed for a "moderate dose" (2 to 20 mcg/kg total dose) range, but may be excessive in this population. In general, young children require higher doses than neonates and infants. With "moderate" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential.

    Intrathecal dosage
    Adults

    10 to 25 mcg as a single intrathecal bolus given in combination with other spinal analgesia to improve intraoperative analgesia.

    For open heart surgery and other complicated procedures where surgery is prolonged and the stress response would be detrimental to the patient's well-being.
    Intravenous and Intramuscular dosage
    Adults

    20 to 50 mcg/kg IV or IM as a total "high" dose for induction. Maintenance dosage (ranging from 25 mcg to one half the initial loading dose) will be dictated by the changes in vital signs which indicate stress and lightening of analgesia. However, the additional dosage selected must be individualized especially if the anticipated remaining operative time is short. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression. The main objective of this dosing is to produce "stress free" anesthesia.

    Adolescents

    20 to 50 mcg/kg IV or IM as a total "high" dose for induction and maintenance. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression. The main objective of this dosing is to produce "stress free" anesthesia.

    Children 2 to 12 years

    2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance per the manufacturer. Larger weight-based dosing recommendations are discussed for "moderate dose" (2 to 20 mcg/kg total dose) and "high dose" (20 to 50 mcg/kg total dose) ranges, but may be excessive in this population. In general, young children require higher doses than older children and adolescents. With "moderate" and "high" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. With "high" doses, postoperative ventilation is essential due to extended postoperative respiratory depression.

    Neonates†, Infants†, and Children 1 year of age†

    Limited data available. 2 to 3 mcg/kg IV or IM as a total "low" dose may be sufficient for induction and maintenance based on dosing in children 2 to 12 years of age. Larger weight-based dosing recommendations are discussed for "moderate dose" (2 to 20 mcg/kg total dose) and "high dose" (20 to 50 mcg/kg total dose) ranges, but may be excessive in this population. In general, young children require higher doses than neonates and infants. With "moderate" and "high" dose anesthesia, respiratory depression will be such that artificial ventilation during anesthesia is necessary and careful observation of ventilation postoperatively is essential. With "high" doses, postoperative ventilation is essential due to extended postoperative respiratory depression.

    For general anesthesia induction when attenuation of the responses to surgical stress is especially important such as during major surgery like open heart surgery or complicated neurological or orthopedic procedures.
    Intravenous or Intramuscular dosage
    Adults

    50 to 100 mcg/kg by slow IV over 1 to 2 minutes or IM may be administered with oxygen and muscle relaxant, without the use of additional anesthetic agents. In certain cases, total doses up to 150 mcg/kg may be necessary to produce adequate anesthetic effect. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.

    Children and Adolescents 2 years and older

    50 to 100 mcg/kg IV or IM as a total dose may be administered with oxygen and muscle relaxant, without the use of additional anesthetic agents. In certain cases, total doses up to 150 mcg/kg may be necessary to produce adequate anesthetic effect. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.

    Neonates†, Infants†, and Children 1 year of age†

    Limited data available for pediatrics 1 year of age and younger. Some experts describe fentanyl doses of 30 to 100 mcg/kg IV for cardiac surgery. Total doses of 50 to 100 mcg/kg IV or IM, administered with oxygen and a muscle relaxant but without the use of additional anesthetic agents may be sufficient based on dosing in children 2 to 12 years of age. In general, young children require higher doses than neonates and infants. Respiratory depression will be such that artificial ventilation during anesthesia is necessary. Postoperative ventilation and observation are essential due to extended postoperative respiratory depression.

    For analgesia and/or sedation maintenance† in mechanically-ventilated intensive care patients.
    Intravenous infusion dosage†
    Adults†

    A loading dose of 1 to 2 mcg/kg IV is usually given, followed by a continuous IV infusion of 1 to 2 mcg/kg/hour. Titrate as needed to desired response. Alternatively, lower infusion rates of 25 to 50 mcg/hour (e.g., 0.5 mcg/kg/hour) can be initiated and the dose titrated upward, as needed.

    For sedation and analgesia prior to rapid-sequence intubation (RSI)†.
    Intravenous dosage
    Adults

    1 to 3 mcg/kg IV over 1 to 2 minutes. Give dose 1 to 3 minutes prior to intubation.

    Infants, Children, and Adolescents

    2 to 3 mcg/kg IV over 1 to 2 minutes is a typical dose; however, a dose range of 1 to 5 mcg/kg has been recommended. Give dose 1 to 3 minutes prior to intubation. In general, infants, older children, and adolescents require lower doses than young children.

    Neonates

    1 to 4 mcg/kg IV over at least 1 to 2 minutes has been recommended.

    For the management of dyspnea† in patients with end-stage cancer or lung disease.
    Nebulized dosage†
    Adults

    A dose of 25 mcg in 2 mL saline via nebulization has been administered to patients with improvements in respiratory rates and oxygen saturation, as well as overall patient perceptions of breathing.

    For procedural sedation† of non-intubated patients during diagnostic, surgical, or other procedures.
    Intravenous dosage
    Adults

    Titrate slowly to achieve the desired effect. The usual dose is 25 mcg IV every 3 to 5 minutes as needed. Premedication with a benzodiazepine may potentiate the response to fentanyl; a reduced fentanyl dose may be needed. NOTE: Fentanyl should be administered as a inducing agent only by those trained in anesthesia. Monitor ventilation closely.

    Adolescents

    0.5 to 2 mcg/kg/dose IV (Max: 50 mcg/dose). May repeat in small increments (e.g., one-half of original dose, no more than 1 mcg/kg/dose) every 3 to 5 minutes as needed; titrate slowly to desired effect. Alternatively, a single dose of 25 to 50 mcg IV may be used. If needed, may repeat the full dose (up to 50 mcg) after 5 minutes. For particularly invasive/painful procedures (e.g., bone marrow aspiration), an additional 25 mcg may be given every 5 minutes for up to 4 to 5 additional doses if needed. Onset of analgesia is approximately 2 to 5 minutes with a duration of 20 to 60 minutes. Respiratory depressive effects usually outlast the opioid effects; close monitoring of ventilation is essential.

    Infants and Children 6 months and older

    0.5 to 2 mcg/kg/dose IV (Max: 50 mcg/dose). May repeat in small increments (e.g., one-half of original dose, no more than 1 mcg/kg/dose) every 3 to 5 minutes as needed; titrate slowly to desired effect. Onset of analgesia is approximately 2 to 5 minutes, and the duration is about 20 to 60 minutes. Respiratory depressive effects usually outlast the opioid effects; close monitoring of ventilation is essential, particularly in younger patients.

    Intranasal dosage†
    Infants, Children, and Adolescents weighing 10 kg or more

    Limited data available; most reports have been in patients weighing 10 kg or more. The injection solution was used for intranasal application as no commercially appropriate product is available. A single dose of 1 to 2 mcg/kg intranasally has been recommended. The usual maximum is 100 mcg/dose intranasally ; however, some experts recommend a maximum of 200 mcg/dose. Studies utilizing an initial dose of 1.4 mcg/kg allowed for additional doses of 15 mcg (0.2 to 1.2 mcg/kg/dose) administered every 5 minutes to a maximum total dose of 3 mcg/kg intranasally. Onset of analgesia is approximately 5 to 10 minutes with a duration of 30 minutes.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4 doses/day of Actiq, Fentora, or Onsolis transmucosal; 800 mcg/dose, 2 doses/break-thru pain episode, and 4 treated episodes/day of Abstral sublingual; 1600 mcg/dose, 2 doses/break-thru pain episode, and 4 treated episodes/day of Subsys sublingual; 800 mcg/dose and 4 doses/day of Lazanda nasal spray; 40 mcg/dose and 80 doses/day with Ionsys; with appropriate dosage titration, there is no maximum dose of other dosage forms.

    Geriatric

    4 doses/day of Actiq, Fentora, or Onsolis transmucosal; 800 mcg/dose, 2 doses/break-through pain episode, and 4 treated episodes/day of Abstral sublingual; 1600 mcg/dose, 2 doses/break-thru pain episode, and 4 treated episodes/day of Subsys sublingual; 800 mcg/dose and 4 doses/day of Lazanda nasal spray; 40 mcg/dose and 80 doses/day with Ionsys; with appropriate dosage titration, there is no maximum dose of other dosage forms.

    Adolescents

    16 to 17 years: 4 units/day of fentanyl transmucosal lozenge (i.e., Actiq). With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.
     
    13 to 15 years: With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.

    Children

    2 to 12 years: With appropriate dosage titration, there is no maximum dose of transdermal or intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.
     
    1 year: With appropriate dosage titration, there is no maximum dose of intravenous fentanyl The safety and efficacy of other dosage forms have not been established.

    Infants

    With appropriate dosage titration, there is no maximum dose of intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.

    Neonates

    With appropriate dosage titration, there is no maximum dose of intravenous fentanyl. The safety and efficacy of other dosage forms have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Transdermal patches: Avoid use in severe hepatic impairment. Reduce the initial transdermal dose by 50% in patients with mild to moderate hepatic impairment and titrate to desired clinical effect.
    Other dosage forms: Fentanyl dosage should be modified based on clinical response and degree of hepatic impairment. No quantitative recommendations are available.

    Renal Impairment

    Transdermal patches: Avoid use in severe renal impairment. Reduce the initial transdermal dose by 50% in patients with mild to moderate renal impairment and titrate to desired clinical effect.
    Other dosage forms: Fentanyl dosage should be modified based on clinical response and degree of renal impairment. No quantitative recommendations are available.

    ADMINISTRATION

     
    Fentanyl products are not bioequivalent and are not interchangeable.

    Oral Administration
    Other Oral Formulations

    Transmucosal and sublingual formulations (Actiq, Fentora, Onsolis, Abstral, and Subsys) are not for use in the management of acute or postoperative pain. These products should only be used in opioid tolerant patients.
    Titrate initial dosage with caution and limit the initial quantity of medication prescribed.
    Advise patients and caregivers that if an overdose is suspected to remove any remaining dosage formulation from the mouth and seek immediate medical help.
     
    Abstral (sublingual tablets) administration:
    If mouth is dry, water may be used to moisten buccal mucosa before administration.
    Dry hands before handling.
    Immediately after removing from blister pack, place tablet on the floor of the mouth directly under the tongue. Allow tablet(s) to dissolve completely.
    Do not use more than 4 tablets at one time.
    Instruct patients to not suck, chew, or swallow tablet. Further, instruct patients to avoid eating or drinking until tablet is dissolved.
    Disposal: Dispose of any unneeded tablets as soon as no longer needed. Remove tablets from the blister cards and flush the tablets down the toilet. Do not dispose of blister cards, cartons, or other packaging in the toilet. Caregivers may also contact the product manufacturer or local DEA office for additional assistance in drug disposal if necessary.
     
    Subsys (sublingual spray) administration:
    Open blister package with scissors immediately prior to use.
    Carefully spray the entire contents of the unit into the mouth under the tongue.
    Dispose of each used unit immediately after use by placing it into one of the disposable bags provided. Seal the bag and discard into a trash container out of the reach of children.
    Consumed units are no longer protected by the child resistant blister package, but may contain enough medicine to be fatal to a child.
    Disposal: Dispose of unused units into the provided charcoal-lined disposal pouch. Hold the charcoal-lined pouch with the opening facing up. Put the nozzle of the spray unit upside-down into the opening of the pouch. Squeeze your fingers and thumb together to spray the contents into the pouch. Dispose of the empty spray unit in a disposal bag. Repeat with any additional unused units. The pouch may be used for disposing of the contents of up to 10 spray units. Seal the pouch and place it in a disposal bag. Seal and discard the disposal bag in the trash out of the reach of children.
     
    Actiq (oral lozenge) administration:
    Place between the cheek and lower gum, occasionally moving from one side of the mouth to the other using the handle. Patients should be instructed to suck but not chew the lozenges.
    Consume over 15 minutes. Longer or shorter consumption times may produce less efficacy.
    Using the handle, remove the unit after it has been consumed or after the patient has achieved the desired level of sedation or is experiencing respiratory depression.
    Disposal: To dispose, remove the drug matrix from the handle by grasping it with tissue and separating it from the handle using a twisting motion. Flush the drug matrix down the toilet. If any of the drug matrix remains on the handle, remove it by placing the handle under warm running water until the drug matrix dissolves. During the disposal process, avoid contract with skin, eyes, or mucous membranes. Wash hands thoroughly when finished. Disposal must be consistent with state and federal regulations.
     
    Fentora (buccal tablet) administration:
    Immediately before use, peel the blister backing away to expose the tablet. To avoid damaging the tablet, do NOT push the tablet through the blister.
    Place the entire tablet either between the cheek and gum above a rear molar tooth or under the tongue. Do not break or split the tablet.
    Allow to dissolve over 30 minutes. Sucking, chewing, or swallowing the tablet or any tablet fragments before 30 minutes have elapsed will produce less efficacy. Any remaining tablet may be swallowed after 30 minutes.
    Have the patient spit out the tablet and rinse their mouth with water if the patient gets very sleepy, dizzy, or has slowed or labored breathing.
    Disposal: Dispose of any unneeded tablets as soon as no longer needed. Remove tablets from the blister cards and flush the tablets down the toilet. Do not dispose of blister cards, cartons, or other packaging in the toilet. Caregivers may also contact the product manufacturer or local DEA office for additional assistance in drug disposal if necessary.
     
    Onsolis (oral dissolving film) administration:
    This medication is applied to the inside of the cheek. Wet the affected area with tongue or rinse of water prior to application.
    Immediately before use, open package with dry hands. Do not cut or tear the film prior to use.
    Using the tip of a dry finger touching the white side of the film, place one film in the mouth with the pink side of the film facing the cheek; hold in place for approximately 5 second to adhere.
    If using more than one film per dose, place films separately using both sides of the mouth as needed; do not overlap or stack films.
    Allow the film(s) to dissolve over 15 to 30 minutes. If chewed and swallowed, lower peak concentrations and bioavailability are expected. Drinking liquids within 5 minutes after application, touching the film with fingers or tongue after placed, or eating before the film has fully dissolved may interfere with patch adherence and drug absorption.
    Disposal: Dispose of any unneeded product as soon as no longer needed. Remove each film from the foil packaging and drop into the toilet, then flush when all unneeded films have placed in the toilet. Do not dispose of foil packs, cartons, or other packaging in the toilet. Caregivers may also contact the product manufacturer or local DEA office for additional assistance in drug disposal if necessary.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
     
    Only individuals trained in the administration of general anesthetics and the management of the respiratory effects of potent opioids should give the drug. Pulse oximetry or some other means for measuring respiratory function is recommended.
    Resuscitative medications, including naloxone, and size-appropriate equipment for bag/valve/mask ventilation and intubation must be readily available.

    Intravenous Administration

    IV Push
    Inject directly into a vein or into the tubing of a freely flowing IV solution slowly over 1—3 minutes. Rapid IV injection of fentanyl may result in apnea.
     
    Continuous IV Infusion
    May dilute in 5% Dextrose injection or 0.9% Sodium Chloride injection.
    Commonly used infusion concentration for adults: 10 mcg/mL. Maximum concentrations of 50 mcg/mL have been used.
    Administer using a controlled-infusion device.
    Adjust dose and infusion rate based on patient response.

    Intramuscular Administration

    Inject into a large muscle mass.
    Aspirate prior to injection to avoid injection into a blood vessel.

    Subcutaneous Administration

    Inject subcutaneously taking care not to inject intradermally.
    Fentanyl has been given as a subcutaneous continuous infusion in children weaning from prolonged sedation.

    Other Injectable Administration

    Epidural Administration
    Epidural administration should only be used by specially trained healthcare professionals.
    May be given as intermittent bolus, continuous infusion, or patient controlled epidural analgesia.
    Prior to administration, an opiate antagonist and facilities for administration of oxygen and control of respiration should be available. The patient should be in a setting where adequate monitoring is possible.
    Placement of epidural catheter and administration should be at a site near the dermatomes covering the field of pain to decrease dose requirements and increase specificity. Fentanyl only produces segmental analgesic effects and should only be used when the catheter tip is close to the incisional dermatome.
     
    Intermittent Epidural Injection
    After ensuring proper placement of the needle or catheter, inject appropriate dose into the epidural space.
    Monitor patient in a fully equipped and staffed environment for at least 24 hours after each dose.
     
    Continuous Epidural Infusion
    A controlled-infusion device must be used. For highly concentrated injections, an implantable controlled-microinfusion device is used. Patients should be monitored in a fully equipped and staffed environment for several days following implantation of the device.
    If dilution of the injection is necessary, 0.9% Sodium Chloride injection is recommended.
    Filling of the infusion device reservoir should only be done by fully trained and qualified healthcare professionals. Strict aseptic technique must be used. Withdraw dose from the ampule through a 5 micron (or smaller pore diameter) microfilter to avoid contamination with glass or other particles. Ensure proper placement of the needle when filling the reservoir to avoid accidental overdose.
    To avoid exacerbation of severe pain and/or reflux of CSF into the reservoir, depletion of the reservoir should be avoided.
    Monitor patient in a fully equipped and staffed environment.

    Topical Administration
    Transdermal Patch Formulations

    Short-acting analgesics may be needed during the initial 24 hours of fentanyl patch application and for breakthrough pain.
    Apply the patch immediately upon removal from the package. Do not use if the pouch seal is broken or the patch is damaged.
    If skin needs preparation, use clear water and clip, do not shave, hair. Do not use soaps, oils, lotions, alcohol, or any other agents that may irritate the skin. Pat skin dry completely before applying patch.
    Apply patch to a flat, intact, non-irritated, and non-irradiated area on the upper torso (e.g., chest, back, flank, or upper arm). Avoid cuts and sores.
    In young children or those with cognitive impairment, place the patch on the upper back to minimize the potential of inappropriate patch removal. Adhesion of the patch should be closely monitored; patients or caregivers should frequently check that the patch has not fallen off, particularly after exercising, bathing, and sleeping.
    Small children have removed patches on sleeping adults or found patches that have fallen off and ingested them or applied them to themselves (e.g., like a bandage); such cases have resulted in fatality. To limit curiosity and/or poor adhesion, patients should not apply patches in the company of young children, to an area of the body where young children can see it, or on areas of frequent movement.
    Do not cut the patch to deliver partial doses. If it is necessary to use a smaller and commercially unavailable dosage, placing impermeable material (e.g., adhesive bandage) on the skin under the patch may block a proportional delivery of the drug.
    Firmly press the patch onto the application site with the palm of the hand for 30 seconds. Make sure contact is complete and edges adhere to the skin. If there is difficulty with adhesion, the patch edges may be taped down with first aid tape or overlayed with a transparent adhesive film dressing (e.g., Tegaderm). Avoid other tight coverings over the patch.
    When applying the patch, touch the adhesive side as little as possible. Exposure to the adhesive matrix may lead to serious adverse events such as respiratory depression and fatal overdose. If unintended skin contact occurs, thoroughly rinse exposed skin with large amounts of water; do not use soap, alcohol, or other solvents as this may enhance the drug's ability to penetrate the skin.
    Wash hands with soap and water immediately after patch application.
    Change patch at the same time of day every 3 days (72 hours); remove any patches in use prior to application of a new patch. Rotate patch application site.
    If the patch falls off before 72 hours of use (including immediately after application) dispose of patch by folding in half so that adhesive side is inward and immediately flushing down the toilet. Use a new patch at a different skin site.
    Avoid contact with unwashed or unclothed application sites; this contact may result in secondary accidental exposure. Accidental exposure may occur during activities such as hugging, bed-sharing, or accidental caregiver skin contact during patch application and removal.
    Avoid exposing the patch application site and surrounding areas to external heat sources (e.g., heating pads, electric blankets, heated water beds, tanning beds, hot baths or saunas, excessive sun exposure, or hot climate). Patients should also be counseled to avoid strenuous exercise, which can heat the body.
    Storage: Instruct patients, caregivers, and family members to keep patches in a secure location out of the reach of children, pets, and others for whom the drug was not prescribed.
    Disposal: Instruct patients, caregivers, and family members to dispose of damaged, used, or any patches remaining from a prescription when they are no longer needed. Improperly disposed of patches can cause serious illness or death, particularly to children or pets who might be inadvertently exposed. Unused patches should be removed from their pouch, folded in half so that the adhesive side is inward, and immediately flushed down the toilet.

    Other Topical Formulations

    Ionsys (iontophoretic transdermal system) administration:
    Apply only 1 system at any given time. Always wear gloves when handling the system.
    Remove the foil pouch and the controller from the tray. Remove the drug unit from the foil pouch and place on a hard, flat surface.
    Assemble the system. Align the matching shapes of the controller and the drug unit. Press on both ends of the device to ensure that the snaps at both ends are fully engaged. One or 2 clicks will be heard when the snaps are fully engaged.
    After assembly, the digital display of the controller will complete a short self-test during which there is 1 audible beep, the red light will blink once, and the digital display will flash the number "88". Following the self-test, the display will show the number 0 and a green light will blink to indicate that the system is ready for application.
    Choose an application site of healthy, unbroken skin on the upper outer arm or chest only. Clip excessive hair. Do not shave as this may irritate the skin.
    Clean the administration site with alcohol and let dry. Do not use soaps, lotions, or other agents.
    Peel off and discard the clear plastic liner covering the adhesive and hydrogels. Do not pull the red tab while preparing to apply the system; the red tab is only to be used during disposal.
    Press and hold the system in place for >= 15 seconds with sticky side facing the skin. Make sure the edges adhere to the skin.
    If the system loosens from the skin, secure it by pressing the edges or use a non-allergenic tape to secure the edges. Do not apply tape if skin is blistered or broken. Apply tape along the long edges of the system. Do not tape over the button, light, or digital display. After taping if the system beeps again, remove it and apply a new system on a different skin site.
    To initiate administration of a dose, the patient should press the recessed button on the top housing of the system twice within 3 seconds. A single beep indicates the start of dose delivery that occurs over 10 minutes. During this time the system is locked-out and another dose cannot be delivered. When dose delivery is complete, the display will show the number of doses delivered.
    Each system will function for 24 hours or 80 doses, whichever comes first. At this time, the green light will turn off and the number of doses delivered will flash on and off. To turn off the digital display, press the dosing button for 6 seconds.
    Remove the system from the patient's skin. Ensure both hydrogels (1 contains fentanyl) remain within the removed system. If a hydrogel becomes separated during removal, use gloves or tweezers to remove it from the skin and properly dispose of in accordance with state and federal regulations for controlled substances.
    Do not touch exposed hydrogel compartments or adhesive. If a hydrogel is touched accidentally, rinse the area with water. Do not use soap.
    If additional analgesia is needed, a new system must be applied to a different site on the upper outer arm or chest.
    Disposal: With gloves on, pull the red tab to separate the red bottom housing containing fentanyl from the system. Fold the red housing in half with the sticky side facing in. Dispose of the red housing per policies for disposal of schedule II drugs or by flushing it down the toilet. Hold the dosing button down until the display goes blank and then dispose of the remaining part of the system containing electronics in waste designated for batteries.

    Inhalation Administration
    Intranasal Inhalation Administration

    Lazanda (intranasal spray) administration:
    Confirm dosage before administration. Lazanda nasal spray is for use in opioid-tolerant adult patients only.
    Prime before using for the first time. Remove the spray bottle from the child-resistant container. Remove the cap from the spray bottle. Aim the spray bottle tip into the provided pouch and depress the finger grips until "click" is heard then repeat for a total of 4 pumps; a green bar should appear in the counting window.The pump will remain primed for up to 5 days after priming or use. If the product has not been used for 5 days, re-prime by spraying once into the pouch. Retain and do not seal the medication pouch. Save the pouch and dispose of it at the appropriate time as directed in the MedGuide. Wash hands after priming.
    Instruct patient on the proper use according to MedGuide illustrated instructions.
    Have patient sit during administration. If nose is runny, blow nose prior to dosing. Place tip of spray of spray bottle in nostril (about 1/2 inch) while closing off other nostril with finger pressed to the side of the nose. Aim for the bridge of nose then depress finger grips until a "click" is heard. Spray may not be felt; an audible "click" and advancement of the dose counter confirm dose administration. Breathe gently in through the nose and out through the mouth one time. Repeat the steps in other nostril if 2 sprays are needed for dose. If 4 sprays are needed for the dose, repeat the steps but alternate nostrils for each spray.
    After administration advise patient to stay sitting for 1 minute and to avoid nose blowing for 30 minutes.
    Return the bottle to the child-resistant container after each use. The bottle (in the child-resistant container) and the pouch should be stored in the cardboard carton and out of the reach of children or pets. Protect from light.
    Wash hands with soap and water after handling the bottle and/or pouch.
    Disposal:
    Discard bottle if no longer needed, if all medication has been used, or if 60 days have passed since first use.
    Follow the directions for proper disposal as indicated in the MedGuide. When a red number "8" appears in the counting window, the bottle is finished. Medicine remaining in the bottle is not enough for an accurate dose.
    Dispose of medication by spraying the bottle into the pouch 4 times. The counter will stay on the red number "8"; no click will be heard once the bottle is empty.
    Seal the pouch and put both the pouch and the empty bottle into the child-resistant container. Twist to close. Throw the child-resistant container into the trash, out of the reach of children and pets.
     
    Fentanyl injectable solution administration:
    NOTE: There is currently no commercially available product that is FDA-approved for pediatric intranasal administration. The Lazanda nasal spray is for opioid-tolerant adults only and has not been studied in pediatric patients.
    Pediatric studies have utilized the injectable solution off-label for intranasal administration at a concentration of 50—300 mcg/ml; however, only the 50 mcg/mL concentration is commercially available in the US.
    In clinical practice, the parenteral solution is administered intranasally via drop installation with a needleless syringe or using a mucosal atomizer device. Use of the mucosal atomizer device improves absorption.
    Clear the nasal passages prior to administration (e.g., suction or have the patient blow their nose).
    Place the patient's head at 45 degrees.
    Administer half of the dose to each nare. Do not use more than 0.5—1 mL of medication per nostril. If a higher dose is required, apply it in 2 separate doses a few minutes apart to allow for adequate absorption of the first dose.
    The patient should remain in a semi-reclined position for several minutes after administration.

    STORAGE

    Generic:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    ABSTRAL:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Actiq:
    - Protect from freezing
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Duragesic:
    - Do not expose product to temperatures above 77 degrees F
    - Store in original unopened pouch
    Fentora:
    - Protect from freezing
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    IONSYS:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container
    Lazanda:
    - Do not freeze
    - Protect from light
    - Store at 77 degrees F
    - Store in original container
    Onsolis:
    - Protect from freezing
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Sublimaze:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original container
    SUBSYS:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The fentanyl iontophoretic transdermal system (Ionsys) is contraindicated in patients with cetylpyridinium chloride hypersensitivity (e.g., Cepacol). Cetylpyridinium chloride is an inactive ingredient in the hydrogels of the product.

    Dental work, headache, migraine, opioid-naive patients, surgery

    Life-threatening hypoventilation resulting in apnea or respiratory arrest may occur at any dose of available non-parenteral fentanyl products in patients not taking chronic opioids and not tolerant to opioids. As such, the following products are contraindicated in opioid-naive patients and in the management of acute and postoperative pain: Abstral, Actiq, Duragesic, Fentora, Lazanda, Onsolis, and Subsys. Patients considered opioid tolerant are those who are using at least 60 mg/day oral morphine, 30 mg/day oral oxycodone, 8 mg/day oral hydromorphone, 25 mg oral oxymorphone/day, 25 mcg transdermal fentanyl/hour, or an equianalgesic dose of another opioid for a week or longer. However, patients who are taking fentanyl as part of ongoing analgesia therapy may be safely continued on the drug following surgery or dental work, if appropriate dosage adjustments are made considering the procedure, other drugs given, and temporary changes in physiology caused by the surgical intervention. Use of Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys is specifically contraindicated in the acute pain conditions of headache and migraine pain; the labeling of these products contains a boxed warning contraindicating such use. Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys are also contraindicated for use in dental pain, while Abstral and Onsolis are contraindicated for emergency room use. Duragesic (transdermal patch) is contraindicated in outpatient or day surgeries because there is no opportunity for proper dose titration, in the management of mild or intermittent pain, for use as an as needed analgesic, and in patients who require opioid analgesia for a short period of time. Parenteral fentanyl is indicated for peri-operative use.

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

    Fentanyl transdermal patches and the Ionsys iontophoretic transdermal system are contraindicated for use in patients with known or suspected paralytic ileus; additionally Ionsys is contraindicated in patients with known or suspected GI obstruction. Due to the effects of opiate agonists on the gastrointestinal tract, fentanyl should be used cautiously in patients with GI disease including GI obstruction, ulcerative colitis, or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Patients with acute ulcerative colitis (UC) or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Although opiate agonists are contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opiate agonists should not be given until the toxic substance has been eliminated.

    Alcoholism, depression, substance abuse

    Fentanyl is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Addiction may occur in patients who obtain fentanyl illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. To discourage abuse, the smallest appropriate quantity of fentanyl needed for appropriate analgesia should be prescribed, and appropriate disposal instructions for unused drug should be given to patients.

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

    Fentanyl transdermal patches and the iontophoretic transdermal system are contraindicated for use in patients with significant respiratory depression or compromise especially in the absence of monitoring and resuscitative equipment, and/or acute or severe bronchial asthma (e.g., status asthmaticus). Additionally, avoid coadministration with other CNS depressants unless no other alternatives are available, as this significantly increases the risk for respiratory depression, low blood pressure, and death. Use appropriate caution when considering opioid therapy in both opioid naive and opioid-tolerant patients with respiratory depression and severe pulmonary disease. Receipt of moderate fentanyl doses in these patients may significantly decrease pulmonary ventilation. Respiratory depression, if left untreated, may cause respiratory arrest and death. Symptoms of respiratory depression include a reduced urge to breathe, a decreased respiratory rate, or deep breaths separated by long pauses (a "sighing" breathing pattern). Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. The long-acting transdermal patches should be reserved for opioid-tolerant patients in whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Do not use as a "prn" or "as needed" analgesic, for acute pain, or if the pain is mild or not expected to persist for an extended period of time. Only patients who are tolerant to around-the-clock opioids should receive transmucosal immediate release products, as non-tolerant patients may experience potentially life-threatening respiratory depression at any dose. Proper dosing and titration are essential; patients should be monitored for respiratory depression, particularly during the first 24 to 72 hours after therapy initiation or a dose increase. When using fentanyl transdermal patches, note the risk of life-threatening respiratory depression is greatest during the first 2 applications following treatment initiation or a dose increase. The risk of respiratory depression persists beyond patch removal due to continued drug absorption; monitor patients for 24 to 72 hours following discontinuation. Caution should be exercised when converting from a different opioid to fentanyl, as initial dose overestimation may lead to fatal overdose in opioid-tolerant patients. In patients with pulmonary disease such as chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, or preexisting respiratory depression, it is recommended that non-opioid analgesics be considered as alternatives to fentanyl, as even usual therapeutic doses may decrease respiratory drive and cause apnea in these patient populations. Extreme caution should also be used in patients with chronic asthma, kyphoscoliosis (a type of scoliosis), hypoxemia, sleep apnea, or obesity, as obesity is a risk factor for obstructive sleep-apnea syndrome and/or decreased respiratory reserve. Careful monitoring is required, particularly when CYP450 3A4 inhibitors or inducers are used concomitantly; concurrent use of a 3A4 inhibitor or discontinuation of a concurrently used 3A4 inducer may increase plasma fentanyl concentrations and potentiate the risk of fatal respiratory depression. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. A high level of vigilant monitoring is recommended and supportive care should be given as needed.

    Potential for overdose or poisoning, requires a specialized care setting, requires an experienced clinician

    Like all opioid analgesics, fentanyl is associated with significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Fentanyl products are not interchangeable and conservative conversion from other opioids to fentanyl is recommended; inappropriate conversion from another opioid agonist or mcg for mcg substitution of one fentanyl product for another may result in fatal overdose with the first dose. Significant pharmacokinetic differences exist between products. Further, the various dosage forms and products are indication specific by design. Transdermal patches should be reserved for management of chronic, severe pain in opioid-tolerants patients who require continuous, around-the-clock, opioid analgesia for an extended period of time. Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys are indicated only for the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Therapy requires an experienced clinician to manage the complex and product-specific treatment. For example, Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys are intended to be prescribed only by oncologists and pain specialists who are knowledgeable of and skilled in the use of schedule II opioids to treat cancer pain. Due to increased fentanyl exposure, increased monitoring is warranted in patients with Grade 1 mucositis receiving the sublingual spray (Subsys). The sublingual spray should be avoided in patients with Grade 2 mucositis unless the benefits outweigh the potential risk of increased respiratory depression. As of December 2011, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program to obtain transmucosal products, which include Abstral, Actiq, Fentora, Lazanda, Onsolis, and Subsys. The TIRF REMS is designed to reduce the risks of abuse, misuse, addiction, and overdose of TIRF medications. Patient and prescriber enrollment is not necessary for inpatient administration (e.g., hospitals, hospices, and long-term care facilities). Likewise, only healthcare professionals who are knowledgeable of the use of opioids for the management of chronic pain should prescribe Duragesic. The Ionsys iontophoretic transdermal system is only available through a restricted program called the Ionsys REMS Program due to the potential for life-threatening respiratory depression from accidental exposure. Ionsys must only be used in the inpatient setting and discontinued before the patient leaves the hospital. Patients should be under medical supervision by healthcare professionals knowledgeable in the use of potent opioids for pain treatment and in the detection and management of hypoventilation. Intravenous fentanyl should only be administered by health care professionals trained in anesthesiology who are familiar with the respiratory effects of potent opioids. In addition, use of anesthetic doses of IV fentanyl requires a specialized care setting where an opiate antagonist, oxygen, and controlled respiration facilities are present.

    Accidental exposure

    Physicians and dispensing pharmacists must specifically question patients or caregivers about the presence of children in the home, either full time or visiting, and counsel them regarding the dangers to children from accidental exposure. Sublingual/transmucosal products (Abstral, Actiq, Fentora, Onsolis, Subsys), nasal spray (Lazanda), transdermal patches (Duragesic), and the iontophoretic transdermal system (Ionsys) contain fentanyl in an amount that can be fatal to a child, pet, or opioid-naive adult. Advise patients and caregivers to wash hands after handling any fentanyl product or packaging and to seek immediate medical help if an accidental exposure occurs. Contact with unwashed or unclothed application sites from the transdermal patch can result in secondary exposure and should be avoided; examples include transfer of the drug to a child's body while hugging, sharing the same bed as the patient, or accidentally sitting on a patch. Keep both used and unused dosage units out of the reach of children or pets. In the event that an Abstral, Actiq, Fentora, Onsolis, Subsys unit is not completely consumed or is not longer needed, it must be properly disposed of as soon as possible. Used patches still may contain enough fentanyl to cause a fatal overdose in a child, adult, or pet. Proper disposal out of the reach or children or pets is essential. Placing a patch in the mouth, chewing it, or swallowing it may cause choking or overdose that may be fatal. Dispose of the fentanyl patch by folding the adhesive side of the patch to itself, then flush the patch down the toilet. Dispose of Abstral, Actiq, Fentora, Onsolis by flushing the medication down the toilet; do not flush foil packages or cartons. Discard fentanyl from Lazanda nasal spray and Subsys sublingual spray according to manufacturer instructions. Also, do not use a patch that is leaking or damaged in any way. Direct exposure to the adhesive gel in patches or to the iontophoretic transdermal system or its hydrogel components may lead to serious adverse events such as respiratory depression and fatal overdose. If accidental skin contact occurs, thoroughly rinse exposed skin with large amounts of water; do not use soap, alcohol, or other solvents to remove the gel because they may enhance the drug's ability to penetrate the skin. If the iontophoretic transdermal system is not handled with gloves by healthcare professionals, accidental overdose may occur.

    MAOI therapy

    The use of fentanyl in patients who have received MAOI therapy within 14 days is not recommended. The potential for interaction appears to be idiosyncratic with poorly understood contributing factors. Although in vitro assay studies have not been undertaken and published literature is inconsistent, it has been postulated that fentanyl may be a weak serotonin reuptake inhibitor. The safe use of fentanyl in patients taking an MAOI has been reported; however, symptoms of serotonin syndrome and death occurred in one patient previously stable on the MAOI tranylcypromine following an uneventful CABG surgery in which fentanyl was administered. It is not known if coadministration of fentanyl with other drugs known to have MAOI activity may result in serotonergic side effects. Caution is advised until more data are available. If used concomitantly, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension are indicated.

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

    Fentanyl and other opiate agonists can cause urinary retention and oliguria due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with bladder obstruction, pelvic tumors, prostatic hypertrophy, urethral stricture, or renal disease. Fentanyl and other opiate agonists can cause urinary retention and oliguria, due to increasing the tension of the detrusor muscle. Patients more prone to these effects include those with bladder obstruction, urethral stricture, pelvic malignancy, or renal disease. Drug accumulation or prolonged duration of action can occur in patients with renal impairment or renal failure and in those patients with hepatic disease. Although fentanyl kinetics are known to be altered as a result due to alterations in metabolic clearance and plasma protein binding, the duration of effect for the initial dose of fentanyl is largely determined by the rate of distribution of the drug. In acute situations, patients require close monitoring to avoid excessive toxicity. Patients with chronic liver disease or renal impairment may require less frequent dosing intervals; titrate doses carefully and more slowly in patients with renal or hepatic impairment. Diminished metabolic clearance may become significant, especially with repeated dosing or with very high single doses. Avoid the use of fentanyl transdermal patches in patients with severe hepatic or renal impairment.

    Brain tumor, CNS depression, head trauma, increased intracranial pressure, seizure disorder, seizures

    Use fentanyl with extreme caution in patients with CNS depression, head trauma, brain tumor, or increased intracranial pressure (ICP). Opiate agonists can compromise the evaluation of neurologic parameters. Rapid administration of high-dose opiate agonists may transiently elevate intracranial pressure and reduce cerebral perfusion pressures. These events are associated with opiate-induced lowering of mean arterial pressure, which stimulates a regulatory response to increase cerebral blood flow leading to increased ICP. Opiate agonist-induced respiratory depression can produce cerebral hypoxia and raise CSF pressure, which is unrelated to but may exaggerate the injury. Use caution in patients with pre-existing seizure disorder. Opiate analgesics, especially in high doses, can precipitate seizures.

    Angina, bradycardia, cardiac arrhythmias, cardiac disease, heart failure, hypotension, orthostatic hypotension, shock

    In anesthesia and critical care, fentanyl is often preferred to morphine due to its ability to attenuate hemodynamic responses and maintain cardiac stability. Fentanyl causes minimal histamine release and therefore has a reduced incidence of hypotension when compared to morphine. However, fentanyl can cause bradycardia, peripheral vasodilation, and hypotension. As such, fentanyl should be used with caution in patients whose ability to maintain blood pressure has already been compromised by hypovolemia, or in those receiving phenothiazines or general anesthetics, which may alter the capacity to sustain adequate pressures. In addition, use fentanyl with caution in patients with circulatory shock as drug-induced vasodilation may further reduce cardiac output and blood pressure. Opiate agonists, including fentanyl, can stimulate a vasovagal response that may produce sinus bradycardia, which could be problematic in patients with angina, pre-existing hypotension, cardiac arrhythmias, cardiac disease, or heart failure. Use fentanyl with caution in patients with pre-existing orthostatic hypotension.

    Children, infants, neonates, premature neonates

    Opiate agonists may be used in children with moderate to severe pain; however, all forms of fentanyl should be used cautiously in children. The age of inclusion of pediatric patients in safety and efficacy studies has varied by fentanyl product. No form of fentanyl is FDA approved for use in neonates, infants, or children < 2 years of age; transdermal patches may be used in opiate-tolerant children >= 2 years of age; fentanyl injection is used commonly in infants and children within intensive care and operative settings but use in children <= 2 years is off-label. Safety and efficacy of transmucosal forms varies by product; safety and efficacy has not been established in patients < 16 years of age for Actiq. Safety and efficacy of Abstral, Fentora, Lazanda, Onsolis, Subsys, and Ionsys have not been established in pediatric patients. Accidental ingestion or unintended exposure by children can be fatal. Instruct patients and caregivers to keep all fentanyl dosage forms out of the reach of children and to properly discard all unneeded product. Neonates and infants < 6 months of age have highly variable clearance of opiate agonists. Therefore, infants younger than 6 months of age may be given opiate agonists but must be closely monitored for apnea until 24 hours after their last dose. Clinical practice guidelines suggest close monitoring of infants up to 1 year of age. Fentanyl clearance may correlate with gestational age and birth weight; premature neonates and neonates < 1 week of age may have significantly slower clearance than other populations. Careful monitoring and titration in small dosage increments is warranted.

    Labor, neonatal opioid withdrawal syndrome, pregnancy

    Fentanyl is classified in FDA pregnancy category C; there have been no well-controlled studies performed in pregnant women. In animal studies, fentanyl use has resulted in inconsistent fertility and fetal effects without dose-dependent or species-dependent correlation. The drug readily crosses the placenta and should only be given to pregnant women if the potential benefit justifies the risk. Although IV and epidural fentanyl are commonly used in labor or obstetric delivery , the manufacturers do not recommend such use citing insufficient data. Infants and neonates are especially sensitive to respiratory depression, so appropriate precautions should be taken if fentanyl is used during labor. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. The risk of respiratory and CNS depression is especially important for premature infants who are particularly sensitive. A specific opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate. Further, the prolonged maternal use of long-acting opioids, such as fentanyl transdermal patches, during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). This syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

    Breast-feeding

    According to the manufacturers, fentanyl is excreted into breast milk and is not recommended for use in women who are breast-feeding. Although the American Academy of Pediatrics (AAP) considers fentanyl to be usually compatible with breast-feeding , the infants of women taking fentanyl while breast-feeding may experience sedation and/or respiratory depression. Symptoms of opioid withdrawal may occur in infants of women who discontinue fentanyl while nursing. Alternative analgesics considered to be usually compatible with breast-feeding by the AAP include acetaminophen, ibuprofen, and morphine. Fentanyl epidural use is generally considered compatible with nursing; when used for analgesia and anesthesia during labor and delivery or when used during other surgery, the healthy term infant can safely nurse as soon as the mother is awake and alert. Observe the infant for somnolence, excessive irritability, or poor feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to maternal drug exposure, healthcare providers are encouraged to report the adverse effect to the FDA.

    Females

    Females may be less sensitive to anesthesia than men and require increased doses of anesthetic agents during surgery. Women tend to report awareness during surgery more frequently than men. In a study of patients receiving propofol, alfentanil and nitrous oxide, women woke significantly faster after anesthesia ended than men. The time to eye opening after anesthesia and response to verbal commands was also shorter in women.

    Geriatric

    Use fentanyl with caution in geriatric or debilitated patients. Geriatric patients are more sensitive to the analgesic effects of fentanyl, as they experience a longer duration of pain relief. Sedation and respiratory depression may result from altered distribution or decreased elimination of the drug. Initial doses may need to be reduced, and doses should be carefully titrated taking into account analgesic effects, adverse reactions, and concomitant drugs that may depress respiration. According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, 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. Individuals receiving palliative care or those in hospice settings are excluded from the Beers Criteria; the balance of benefits and harms of medication management for these patients may differ from those of the general population of older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). The Guidelines caution that opioids may cause constipation, nausea, vomiting, sedation, lethargy, weakness, confusion, dysphoria, physical and psychological dependency, hallucinations, and unintended respiratory depression, especially in individuals with compromised pulmonary function. These adverse effects can lead to other consequences such as falls. In addition, the initiation of longer-acting opioids (e.g., transdermal fentanyl) is not recommended unless shorter-acting opioids have been unsuccessful, or titration of shorter-acting doses has established a clear daily dose of opioid analgesic that can be provided by using a long-acting form.

    Biliary tract disease, pancreatitis

    As with other opiate agonists, fentanyl may cause spasm of the sphincter of Oddi. Fentanyl should be used with caution in patients with biliary tract disease, including acute pancreatitis, or undergoing biliary tract surgery. Increases in serum amylase may occur.

    Abrupt discontinuation

    Abrupt discontinuation of prolonged fentanyl therapy can result in withdrawal symptoms. Gradually taper patients off prolonged fentanyl therapy to avoid a withdrawal reaction. Withdrawal reactions may be delayed in some patients on fentanyl transdermal formulations because of the extended fentanyl release from the skin into the systemic circulation following removal of the patch. Avoid use of partial agonists (e.g., buprenorphine), mixed agonist-antagonists (e.g., nalbuphine), or pure antagonists (e.g., naloxone) in patients physically dependent on opioids, as an acute withdrawal syndrome may precipitate. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and on the administered dose of the concomitant drug. If treatment of respiratory depression in an individual physically dependent on opioids is necessary, administer the opioid antagonist with extreme care; titrate the antagonist dose by using smaller than usual doses. In addition, the use of partial agonists or mixed agonist/antagonists in patients who have received or are receiving fentanyl may reduce the analgesic effect of fentanyl.

    Driving or operating machinery

    Any patient receiving an opiate agonist, including fentanyl, should be warned about the possibility of sedation and to use caution when driving or operating machinery.

    Anticoagulant therapy, coagulopathy, epidural administration, infection, intrathecal administration, thrombocytopenia

    Use of injectable fentanyl by epidural administration and/or intrathecal administration may not be appropriate in patients with infection at the injection site or documented bacteremia, platelet abnormalities, thrombocytopenia < 100,000/mm3, increased bleeding time, uncontrolled coagulopathy, anticoagulant therapy, presence of tumor at the injection site and any other drug therapy or medical condition that may contraindicate administration of injectable fentanyl by these routes. Further, the safety and efficacy of epidural or intrathecal administration of injectable fentanyl in children have not been determined. Consider alternate routes or sites of administration in such patients.

    Opiate agonist hypersensitivity

    Although true opiate agonist hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to fentanyl should not receive other opiate agonists of the phenylpiperidine subclass (meperidine, sufentanil). It is possible to treat these patients with an opioid agonist from the phenanthrene subclass (including oxycodone, codeine and hydromorphone) or the diphenylheptane subclass (methadone).

    Ambient temperature increase, fever, heating pad, skin abrasion, sunlight (UV) exposure

    Application of transdermal patches to areas of preexisting skin abrasion can subject the patient to an additional risk of local adverse effects; patches are only for application to intact skin. Also, use only intact patches; use of damaged or cut patches can lead to a potentially fatal fentanyl dose due to rapid drug release. Serum concentrations of fentanyl could increase by approximately one-third in patients with fever > 104 degrees F (40 degrees C) due to temperature dependent increase in fentanyl release from the transdermal system and increased skin permeability. Patients with fever who are wearing fentanyl transdermal patches should be carefully monitored for increased side effects and dosage adjustments may be necessary. Patients should avoid strenuous exertion that may increase core body temperature. Application of heat over fentanyl transdermal patches worn by healthy adults increased fentanyl mean serum concentration (Cmax) by 61% and mean systemic exposure (AUC) by 120%. Fatal overdose attributable to heat exposure has occurred. Patients should be advised to avoid exposing the transdermal application site to direct external heat sources, such as a heating pad, electric blankets, heat lamps, saunas, hot tubs, heated water beds, hot baths, sunbathing (including tanning beds and other sunlight (UV) exposure), conditions of ambient temperature increase, etc.

    Ocular exposure

    In order to minimize risk of ocular exposure and/or unintended topical or mucous membrane exposure during the use or disposal of fentanyl transdermal patches, nasal spray, and transmucosal dosage forms advise patients and caregivers in correct administration technique and to wash hands after handling. Thoroughly rinse exposed area (e.g., skin, eyes) with water after any accidental exposure to avoid absorption and possibility of side effects; obtain medical attention should any adverse events develop.

    Dental disease, diabetes mellitus, stomatitis

    Transmucosal (and/or sublingual) fentanyl products may be inappropriate for certain patients with mouth inflammation (mucous membrane stomatitis) or certain types of oral or dental disease. Such products may worsen mucous membrane pain and oral inflammation, or may increase fentanyl exposure and thus increase the risk for respiratory depression. Although stomatitis has been reported among patients receiving fentanyl oral lozenges (Actiq) or sublingual tablets (Abstral), use was not specifically studied in patients with pre-existing mucositis or stomatitis. The safety and efficacy of the buccal tablet (Fentora) and orally dissolving film (Onsolis) have not been studied in patients with mucositis more severe than Grade 1. Use of the sublingual spray (Subsys) is not recommended in patients with more severe mucositis than Grade 1 unless the benefits outweigh the potential risks; compromised mucosal integrity may increase fentanyl exposure and increased monitoring is warranted in those with Grade 1 mucositis. The Actiq brand fentanyl oral lozenge contains approximately 2 grams of sugar per unit; frequent consumption of sugar-containing products may increase the risk of dental disease, especially dental caries. The occurrence of dry mouth associated with the use of opiate agonists medications, such as fentanyl, may add to the risk. Therefore, patients using these fentanyl oral lozenges should consult their dentist to ensure appropriate oral hygiene; patients with diabetes mellitus should be advised of the sugar content in each lozenge unit.

    Defibrillation (cardioversion), magnetic resonance imaging (MRI)

    Because some fentanyl transdermal patches may contain aluminum or other metal components, patients should be instructed to remove the patch before undergoing magnetic resonance imaging (MRI). Metal components contained in the backing of some transdermal systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered. The iontophoretic transdermal system (Ionsys) contains metal parts and must be removed and disposed of prior to MRI scans. In the case of inadvertent exposure, monitor patients for signs of CNS or respiratory depression, as it is not known if MRI exposure increases the release of fentanyl. Remove Ionsys prior to cardioversion, defibrillation (cardioversion), X-ray, CT scan, or diathermy as electromagnetic fields in these procedures may damage the system. Radio-opaque components in Ionsys may interfere with X-ray or CT scans; interference does not occur with other electromechanical devices such as pacemakers or electrical monitoring equipment. Avoid exposing Ionsys to electronic security systems. Contact with synthetic materials (e.g., carpet) may increase the possibility of electrostatic discharge and damage. Use of Ionsys near radio frequency identification transmitters or other communications equipment may damage the system; the recommended separation distances between Ionsys and the equipment ranges from 0.12—23 meters. Recommended separation distances may be found in the FDA-approved product labeling. If exposure to these devices or procedures occur and Ionsys does not appear to function normally, remove and replace with a new system.

    Adrenal insufficiency, hypothyroidism, myxedema

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

    ADVERSE REACTIONS

    Severe

    hearing loss / Delayed / 0-1.0
    ocular hemorrhage / Delayed / 0-1.0
    oliguria / Early / 0-1.0
    seizures / Delayed / 1.0
    hematemesis / Delayed / 1.0
    GI obstruction / Delayed / 1.0
    GI bleeding / Delayed / 1.0
    cardiac arrest / Early / 1.0
    bradycardia / Rapid / 1.0
    thrombosis / Delayed / 1.0
    exfoliative dermatitis / Delayed / 2.0
    pancytopenia / Delayed / 1.0
    bone fractures / Delayed / 1.0
    renal failure (unspecified) / Delayed / 1.0
    pulmonary embolism / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    pneumothorax / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    chest wall rigidity / Rapid / Incidence not known
    ileus / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    skin necrosis / Early / Incidence not known
    SIADH / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    serotonin syndrome / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 0-26.0
    hypokalemia / Delayed / 0-15.0
    hypoventilation / Rapid / 0-4.0
    respiratory depression / Rapid / 0-1.0
    aphasia / Delayed / 0-1.0
    myoclonia / Delayed / 0-1.0
    fecal incontinence / Early / 0-1.0
    angina / Early / 0-1.0
    phlebitis / Rapid / 0-1.0
    hot flashes / Early / 0-1.0
    prolonged bleeding time / Delayed / 0-1.0
    myopathy / Delayed / 0-1.0
    synovitis / Delayed / 0-1.0
    amblyopia / Delayed / 0-1.0
    hypoglycemia / Early / 0-1.0
    tolerance / Delayed / 10.0
    dyspnea / Early / 1.0
    depression / Delayed / 1.0
    dysphonia / Delayed / 1.0
    confusion / Early / 1.0
    amnesia / Delayed / 1.0
    dysphoria / Early / 1.0
    peripheral neuropathy / Delayed / 1.0
    migraine / Early / 1.0
    euphoria / Early / 1.0
    hallucinations / Early / 1.0
    dysphagia / Delayed / 1.0
    stomatitis / Delayed / 1.0
    glossitis / Early / 1.0
    ascites / Delayed / 1.0
    gastritis / Delayed / 1.0
    sinus tachycardia / Rapid / 1.0
    edema / Delayed / 1.0
    hypertension / Early / 1.0
    peripheral edema / Delayed / 1.0
    chest pain (unspecified) / Early / 1.0
    hypotension / Rapid / 1.0
    blurred vision / Early / 1.0
    urinary retention / Early / 1.0
    bleeding / Early / 1.0
    skin ulcer / Delayed / 1.0
    erythema / Early / 1.0
    oral ulceration / Delayed / 1.0
    neutropenia / Delayed / 1.0
    thrombocytopenia / Delayed / 1.0
    anemia / Delayed / 1.0
    leukopenia / Delayed / 1.0
    hyponatremia / Delayed / 1.0
    impotence (erectile dysfunction) / Delayed / 1.0
    bone pain / Delayed / 1.0
    elevated hepatic enzymes / Delayed / 1.0
    jaundice / Delayed / 1.0
    dehydration / Delayed / 1.0
    hyperglycemia / Delayed / 1.0
    hypocalcemia / Delayed / 1.0
    hypercalcemia / Delayed / 1.0
    hypoalbuminemia / Delayed / 1.0
    hypomagnesemia / Delayed / 1.0
    candidiasis / Delayed / 1.0
    lymphadenopathy / Delayed / 1.0
    conjunctivitis / Delayed / 1.0
    urinary incontinence / Early / 1.0
    vaginitis / Delayed / 1.0
    dysuria / Early / 1.0
    vaginal bleeding / Delayed / 1.0
    hematuria / Delayed / 1.0
    hypoxia / Early / Incidence not known
    wheezing / Rapid / Incidence not known
    hemoptysis / Delayed / Incidence not known
    ataxia / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    burns / Early / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    skin erosion / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    ejaculation dysfunction / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    akathisia / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known

    Mild

    vomiting / Early / 0-33.0
    rash (unspecified) / Early / 0-8.0
    abnormal dreams / Early / 0-3.0
    miosis / Early / 0-1.0
    cheilitis / Delayed / 0-1.0
    maculopapular rash / Early / 0-1.0
    urticaria / Rapid / 0-1.0
    skin hyperpigmentation / Delayed / 0-1.0
    skin discoloration / Delayed / 0-1.0
    polyuria / Early / 0-1.0
    nocturia / Early / 0-1.0
    bladder discomfort / Early / 0-1.0
    increased urinary frequency / Early / 0-1.0
    cough / Delayed / 1.0
    malaise / Early / 1.0
    insomnia / Early / 1.0
    drowsiness / Early / 1.0
    tremor / Early / 1.0
    asthenia / Delayed / 1.0
    hypoesthesia / Delayed / 1.0
    agitation / Early / 1.0
    paranoia / Early / 1.0
    headache / Early / 1.0
    lethargy / Early / 1.0
    fatigue / Early / 1.0
    paresthesias / Delayed / 1.0
    dizziness / Early / 1.0
    vertigo / Early / 1.0
    emotional lability / Early / 1.0
    anxiety / Delayed / 1.0
    anorexia / Delayed / 1.0
    abdominal pain / Early / 1.0
    dysgeusia / Early / 1.0
    dyspepsia / Early / 1.0
    gastroesophageal reflux / Delayed / 1.0
    eructation / Early / 1.0
    flatulence / Early / 1.0
    diarrhea / Early / 1.0
    nausea / Early / 1.0
    syncope / Early / 1.0
    pallor / Early / 1.0
    pruritus / Rapid / 1.0
    xerophthalmia / Early / 1.0
    gingivitis / Delayed / 1.0
    xerostomia / Early / 1.0
    nasal congestion / Early / 1.0
    rhinorrhea / Early / 1.0
    nasal irritation / Early / 1.0
    hyperhidrosis / Delayed / 1.0
    alopecia / Delayed / 1.0
    night sweats / Early / 1.0
    skin irritation / Early / 1.0
    epistaxis / Delayed / 1.0
    weakness / Early / 1.0
    chills / Rapid / 1.0
    muscle cramps / Delayed / 1.0
    ecchymosis / Delayed / 1.0
    back pain / Delayed / 1.0
    fever / Early / 1.0
    weight loss / Delayed / 1.0
    myalgia / Early / 1.0
    arthralgia / Delayed / 1.0
    ptosis / Delayed / 1.0
    parosmia / Delayed / 1.0
    tinnitus / Delayed / 1.0
    laryngitis / Delayed / 1.0
    infection / Delayed / 1.0
    rhinitis / Early / 1.0
    sinusitis / Delayed / 1.0
    influenza / Delayed / 1.0
    urinary urgency / Early / 1.0
    hiccups / Early / Incidence not known
    hyperventilation / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    dental caries / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    xerosis / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    hypothermia / Delayed / Incidence not known
    shivering / Rapid / Incidence not known
    restlessness / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Acetaminophen; Butalbital: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Concomitant use of fentanyl with other CNS depressants, such as dichloralphenazone, can potentiate the effects of fentanyl on respiration, CNS depression, sedation, and hypotension.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Major) Avoid the concomitant use of pentazocine and opiate agonists, such as fentanyl. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Pentazocine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acetaminophen; Tramadol: (Major) Concomitant use of tramadol increases the seizure risk in patients taking opiate agonists. Also, tramadol can cause additive CNS depression and respiratory depression when used with opiate agonists; avoid concurrent use whenever possible. If used together, extreme caution is needed, and a reduced tramadol dose is recommended.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity such as opiate agonists. In addition, aldesleukin, IL-2, is a CYP3A4 inhibitor and may increase oxycodone plasma concentrations and related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patients for an extended period and adjust oxycodone dosage as necessary.
    Aliskiren; Amlodipine: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Alosetron: (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alprazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Amide local anesthetics: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amiloride: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Amiodarone: (Moderate) Amiodarone inhibits CYP3A4. When fentanyl is administered to patients receiving amiodarone, the incidence of bradycardia and other adverse cardiovascular effects was much higher than in patients not on amiodarone who received fentanyl. Due to the extremely long elimination half-life of amiodarone, fentanyl should be used cautiously in patients who are receiving amiodarone or who have received amiodarone in the preceding month.
    Amitriptyline: (Moderate) Use caution in the use of fentanyl with tricyclic antidepressants (TCAs) because they can cause additive sedation, possible respiratory depression, or additive hypotension. Hypoventilation and profound sedation or hypotension may occur in severe cases. Additive effects on intestinal motility (constipation) or bladder function may also occur. Following the administration of fentanyl, the dose of other CNS depressant drugs should generally be reduced. If a patient is receiving fentanyl for chronic pain and the patient is taking a TCA, initiate fentanyl with care. Caution should also be observed when administering TCAs with opiates having serotonergic properties such as fentanyl. Serotonin syndrome may rarely occur and is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma). If serotonin syndrome is suspected, both the TCA and concurrent serotonergic agents should be discontinued.
    Amitriptyline; Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Use caution in the use of fentanyl with tricyclic antidepressants (TCAs) because they can cause additive sedation, possible respiratory depression, or additive hypotension. Hypoventilation and profound sedation or hypotension may occur in severe cases. Additive effects on intestinal motility (constipation) or bladder function may also occur. Following the administration of fentanyl, the dose of other CNS depressant drugs should generally be reduced. If a patient is receiving fentanyl for chronic pain and the patient is taking a TCA, initiate fentanyl with care. Caution should also be observed when administering TCAs with opiates having serotonergic properties such as fentanyl. Serotonin syndrome may rarely occur and is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma). If serotonin syndrome is suspected, both the TCA and concurrent serotonergic agents should be discontinued.
    Amlodipine: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amlodipine; Atorvastatin: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amlodipine; Benazepril: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amlodipine; Olmesartan: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amlodipine; Telmisartan: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amlodipine; Valsartan: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Amobarbital: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Amoxapine: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as amoxapine, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as clarithromycin, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as clarithromycin, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Amphetamines: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and fentanyl. Patients receiving fentanyl and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and fentanyl should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Amprenavir: (Moderate) Amprenavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4, such as fentanyl. Although drug interaction studies have not been conducted, the serum concentrations of fentanyl may be increased with concomitant administration of amprenavir.
    Amyl Nitrite: (Moderate) Administration of nitrates such as amyl nitrite to patients receiving other hypotension-producing agents, such as opiate agonists, can cause additive hypotensive or orthostatic effects.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
    Aprepitant, Fosaprepitant: (Major) Use caution if fentanyl and aprepitant, fosaprepitant are used concurrently and monitor for an increase in fentanyl-related adverse effects, including respiratory depression, for several days after administration of a multi-day aprepitant regimen. Fentanyl 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 fentanyl. 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.
    Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including opiate agonists.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Aspirin, ASA; Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Atazanavir: (Major) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as fentanyl. Fentanyl should be used with extreme caution if deemed appropriate for use in a patient taking atazanavir. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Atazanavir; Cobicistat: (Major) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as fentanyl. Fentanyl should be used with extreme caution if deemed appropriate for use in a patient taking atazanavir. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension. (Moderate) The plasma concentrations of fentanyl may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while fentanyl is a CYP3A4 and P-gp substrate.
    Atenolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Atenolol; Chlorthalidone: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Atracurium: (Major) Although adequate sedation and analgesia must accompany the use of neuromscular blockers, coadministration of opioids such as fentanyl may enhance neuromuscular blockade and produce an increased degree of respiratory depresssion. Monitor patients for signs of respiratory depression that may be greater than otherwise expected. A dose reduction of one or both drugs may be warranted.
    Atropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Difenoxin: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Diphenoxylate: (Major) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Edrophonium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Azelastine: (Major) 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: (Major) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azilsartan; Chlorthalidone: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Azithromycin: (Moderate) Fentanyl is a substrate of P-glycoprotein (P-gp) and azithromycin is a P-gp inhibitor; therefore, fentanyl concentrations could be increased with coadministration. Monitor patients for increased side effects if these drugs are given together.
    Baclofen: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Barbiturates: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Belladonna; Opium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Bendroflumethiazide; Nadolol: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benztropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bepridil: (Moderate) Severe hypotension has occurred with coadministration of calcium-channel blockers and fentanyl, which may be associated with increased fluid volume requirements.
    Beta-blockers: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Betaxolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Bethanechol: (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bisoprolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering fentanyl with boceprevir due to an increased potential for fentanyl-related adverse events. If fentanyl dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of fentanyl. Fentanyl is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated fentanyl plasma concentrations.
    Bosentan: (Moderate) Drugs that induce the hepatic cytochrome P450 3A4 isoenzyme, such as bosentan, may induce fentanyl metabolism and thus, may decrease the effectiveness of fentanyl, a substrate of CYP3A4.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including opiate agonists.
    Brigatinib: (Moderate) Monitor for decreased efficacy of fentanyl if coadministration with brigatinib is necessary. Fentanyl is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of fentanyl may decrease.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Bumetanide: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as fentanyl. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Buprenorphine; Naloxone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as fentanyl. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist. (Major) Naloxone is the pharmacologic opposite of fentanyl. Naloxone can block the actions of fentanyl and, if administered to patients who are dependent on fentanyl, can produce acute withdrawal and/or allow pain to recur.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. 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.
    Buspirone: (Major) Concomitant use of fentanyl with other CNS depressants, such as buspirone, can potentiate the effects of fentanyl on respiration, CNS depression, sedation, and hypotension.
    Butabarbital: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Butorphanol: (Major) Avoid the concomitant use of butorphanol and opiate agonists, such as fentanyl. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. 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.
    Cabozantinib: (Moderate) Monitor for an increase in fentanyl-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of fentanyl may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and fentanyl is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Capsaicin; Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Carbamazepine: (Moderate) Inducers of CYP3A4 such as carbamazepine may induce the hepatic metabolism of opiate agonists, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after opiate therapy has begun in patients who are opiate tolerant. Clinicians should be alert to changes in the effect of the opioid agonist. Opiate doses may need to be increased if carbamazepine is added. Conversely, doses may need to be decreased if carbamazepine is discontinued.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Carbinoxamine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including opiate agonists.
    Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Carteolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Carvedilol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Ceritinib: (Moderate) Concurrent use of fentanyl with ceritinib may increase the risk of increased fentanyl-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of fentanyl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ceritinib in a patient taking fentanyl may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If ceritinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate of CYP3A4. Ceritinib is a CYP3A4 inhibitor.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlordiazepoxide; Clidinium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Chloroprocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlorothiazide: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Chlorpheniramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Chlorpromazine: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as phenothiazines, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring are recommended to ensure the absence of hypotension and respiratory depression.
    Chlorthalidone: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Chlorthalidone; Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists. (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Chlorzoxazone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Cimetidine: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as cimetidine, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Ciprofloxacin: (Moderate) The plasma concentrations of fentanyl may be elevated when administered concurrently with ciprofloxacin. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor, while fentanyl is a CYP3A4 substrate.
    Cisatracurium: (Major) Although adequate sedation and analgesia must accompany the use of neuromscular blockers, coadministration of opioids such as fentanyl may enhance neuromuscular blockade and produce an increased degree of respiratory depresssion. Monitor patients for signs of respiratory depression that may be greater than otherwise expected. A dose reduction of one or both drugs may be warranted.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
    Clarithromycin: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as clarithromycin, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Clobazam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clomipramine: (Moderate) Use caution in the use of fentanyl with tricyclic antidepressants (TCAs) because they can cause additive sedation, possible respiratory depression, or additive hypotension. Hypoventilation and profound sedation or hypotension may occur in severe cases. Additive effects on intestinal motility (constipation) or bladder function may also occur. Following the administration of fentanyl, the dose of other CNS depressant drugs should generally be reduced. If a patient is receiving fentanyl for chronic pain and the patient is taking a TCA, initiate fentanyl with care. Caution should also be observed when administering TCAs with opiates having serotonergic properties such as fentanyl. Serotonin syndrome may rarely occur and is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma). If serotonin syndrome is suspected, both the TCA and concurrent serotonergic agents should be discontinued.
    Clonazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clozapine: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as clozapine, can potentiate the effects of fentanyl on respiration, CNS depression, sedation, and hypotension. Concurrent use of clozapine and opiates may also lead to reduced intestinal motility or bladder function.
    Cobicistat: (Moderate) The plasma concentrations of fentanyl may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while fentanyl is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of fentanyl may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while fentanyl is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of fentanyl may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while fentanyl is a CYP3A4 and P-gp substrate.
    Codeine; Phenylephrine; Promethazine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    COMT inhibitors: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Conivaptan: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and fentanyl, a CYP3A4/P-gp substrate. Concurrent use may result in elevated fentanyl serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as fentanyl, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with fentanyl. Treatment with fentanyl may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Moderate) Concomitant use of fentanyl with crizotinib may increase fentanyl plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of crizotinib could decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for both CYP3A4 and P-glycoprotein (P-gp). Crizotinib is a moderate inhibitor of CYP3A4 and an inhibitor of P-gp.
    Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
    Cyclobenzaprine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Daclatasvir: (Moderate) Systemic exposure of fentanyl, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of fentanyl; monitor patients for potential adverse effects.
    Dalfopristin; Quinupristin: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as streptogramins, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects. Close monitoring for oversedation, respiratory depression, and hypotension is warranted in patients receiving any CYP3A4 inhibitor concomitantly with fentanyl.
    Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically reduce the metabolism of other CYP3A4 substrates incuding fentanyl. Patients receiving these fentanyl should be closely monitored for toxicity if danazol is added to therapy. Conversely, a dose adjustment of either drug may be necessary if danazol therapy is discontinued.
    Dantrolene: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Darifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Darunavir: (Major) The plasma concentrations of fentanyl may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Fentanyl is a CYP3A4 substrate. Darunavir is a substrate/inhibitor of CYP3A4.
    Darunavir; Cobicistat: (Major) The plasma concentrations of fentanyl may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Fentanyl is a CYP3A4 substrate. Darunavir is a substrate/inhibitor of CYP3A4. (Moderate) The plasma concentrations of fentanyl may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while fentanyl is a CYP3A4 and P-gp substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Use fentanyl in combination with ritonavir with extreme caution; ritonavir can significantly inhibit fentanyl's metabolism. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for signs of excessive fentanyl exposure such as oversedation, respiratory depression, and hypotension. Fentanyl is metabolized mainly by the cytochrome P450 (CYP) 3A4 isoenzyme and is a P-glycoprotein (P-gp) substrate. Ritonavir is a potent CYP3A4 inhibitor, and also inhibits P-gp. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%).
    Dasatinib: (Moderate) Dasatinib is a time-dependent, weak inhibitor of CYP3A4. Therefore, caution is warranted when drugs that are metabolized by this enzyme like fentanyl are administered concurrently with dasatinib as increased adverse reactions may occur.
    Delavirdine: (Major) Delavirdine is a potent inhibitor of CYP3A4. Increased concentrations of the CYP3A4 substrate fentanyl are expected with coadministration. Fentanyl should be used with extreme caution if deemed appropriate for use in a patient taking delavirdine. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desipramine: (Moderate) Use caution in the use of fentanyl with tricyclic antidepressants (TCAs) because they can cause additive sedation, possible respiratory depression, or additive hypotension. Hypoventilation and profound sedation or hypotension may occur in severe cases. Additive effects on intestinal motility (constipation) or bladder function may also occur. Following the administration of fentanyl, the dose of other CNS depressant drugs should generally be reduced. If a patient is receiving fentanyl for chronic pain and the patient is taking a TCA, initiate fentanyl with care. Caution should also be observed when administering TCAs with opiates having serotonergic properties such as fentanyl. Serotonin syndrome may rarely occur and is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma). If serotonin syndrome is suspected, both the TCA and concurrent serotonergic agents should be discontinued.
    Desloratadine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    Desloratadine; Pseudoephedrine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including opiate agonists. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering desvenlafaxine with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring is recommended during co-administration of fentanyl and desvenlafaxine for signs and symptoms of serotonin syndrome or other serious effects.
    Deutetrabenazine: (Major) Concomitant use of opiate agonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with deutetrabenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking deutetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. If deutetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with opiate agonists likely to lead to an enhancement of CNS depression.
    Dexpanthenol: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Dextromethorphan; Quinidine: (Moderate) Quinidine increases fentanyl serum concentrations by inhibiting intestinal P-glycoprotein (P-gp). Receipt of fentanyl 2.5 mcg/kg orally 1 hour after a single dose of immediate-release quinidine 600 mg led to a fentanyl mean area under the plasma concentration-time curve (AUC) of 2.34 +/- 0.63 ng x hour/mL as compared with 0.9 +/- 0.47 ng x hour/mL with placebo. Elevated fentanyl serum concentrations can result in an increase in the pharmacologic effects of fentanyl, such as CNS or respiratory depression.
    Diazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dicyclomine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Diltiazem: (Major) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers. In addition, diltiazem inhibits CYP3A4, which may decrease hepatic metabolism of CYP3A4 substrates, such as fentanyl.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Diphenhydramine; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Diuretics: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as fentanyl. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Dorzolamide; Timolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Doxacurium: (Major) Although adequate sedation and analgesia must accompany the use of neuromscular blockers, coadministration of opioids such as fentanyl may enhance neuromuscular blockade and produce an increased degree of respiratory depresssion. Monitor patients for signs of respiratory depression that may be greater than otherwise expected. A dose reduction of one or both drugs may be warranted.
    Doxepin: (Moderate) Use caution in the use of fentanyl with tricyclic antidepressants (TCAs) because they can cause additive sedation, possible respiratory depression, or additive hypotension. Hypoventilation and profound sedation or hypotension may occur in severe cases. Additive effects on intestinal motility (constipation) or bladder function may also occur. Following the administration of fentanyl, the dose of other CNS depressant drugs should generally be reduced. If a patient is receiving fentanyl for chronic pain and the patient is taking a TCA, initiate fentanyl with care. Caution should also be observed when administering TCAs with opiates having serotonergic properties such as fentanyl. Serotonin syndrome may rarely occur and is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma). If serotonin syndrome is suspected, both the TCA and concurrent serotonergic agents should be discontinued.
    Dronabinol, THC: (Moderate) Concomitant use of opiate agonists and other CNS depressants such as dronabinol, THC may result in respiratory depression, CNS depression, and/or hypotension. Prior to concurrent use of opiate agonists in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment is necessary, reduce the dose of 1 or both drugs. When levorphanol is used with dronabinol, reduce the initial levorphanol dose by approximately 50% or more.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A; dronedarone also inhibits P-gp. Fentanyl is a substrate for CYP3A4 and P-gp. The concomitant administration of dronedarone with CYP3A4 and P-gp substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Droperidol: (Major) Concomitant use of fentanyl with other CNS depressants may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable. Also, concurrent use of fentanyl and droperidol may decrease pulmonary arterial pressure, and if the EEG is used for postoperative monitoring, the return to normalcy of the EEG pattern may be slow. Further, if fentanyl and droperidol are used together, fluid replacement for correction of hypotension may be needed; do not administer epinephrine for hypotension, as epinephrine may paradoxically decrease the blood pressure.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering duloxetine with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring is recommended during co-administration of fentanyl and duloxetine for signs and symptoms of serotonin syndrome or other serious effects.
    Efavirenz: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as fentanyl. Fentanyl should be used with extreme caution if deemed appropriate for use in a patient taking efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as fentanyl. Fentanyl should be used with extreme caution if deemed appropriate for use in a patient taking efavirenz.
    Elbasvir; Grazoprevir: (Moderate) Administering fentanyl with elbasvir; grazoprevir may result in elevated fentanyl plasma concentrations. Fentanyl is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Minor) Coadministration of fentanyl and eliglustat may result in increased plasma concentrations of fentanyl. Monitor patients closely for fentanyl-related adverse effects including respiratory depression, and consider reducing the fentanyl dosage and titrating to clinical effect. Fentanyl is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Opiate agonists are a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of the opiate agonist is possible. Monitor patients for adverse reactions if eltrombopage is administered with an opiate agonist.
    Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as 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; Felodipine: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Enflurane: (Major) Concomitant use of fentanyl with other CNS depressants, such as general anesthetics, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Enzalutamide: (Moderate) Monitor for reduced efficacy of fentanyl and signs of opioid withdrawal if coadministration with enzalutamide is necessary; consider increasing the dose of fentanyl as needed. If enzalutamide is discontinued, consider a dose reduction of fentanyl and frequently monitor for signs or respiratory depression and sedation. Fentanyl is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease fentanyl levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Erythromycin: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as erythromycin, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Erythromycin; Sulfisoxazole: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as erythromycin, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
    Esmolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Estazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Eszopiclone: (Moderate) Concomitant use of fentanyl with eszopiclone may cause respiratory depression, hypotension, and profound sedation. A coma could result in some circumstances. 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. If concurrent use is desired, significantly reduce the dose of fentanyl and/or eszopiclone Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable
    Ethacrynic Acid: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    Etomidate: (Major) Concomitant use of fentanyl with other CNS depressants, such as etomidate, may cause enhanced respiratory depression, hypotension, and profound sedation. Less etomidate is generally required under these circumstances. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor and fentanyl is a CYP3A4 and PGP substrate. Caution is warranted if these drugs are coadministered.
    Everolimus: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of everolimus with fentanyl is necessary; consider a reduced dose of fentanyl if appropriate. If everolimus is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like everolimus can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If everolimus is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Felodipine: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flavoxate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as opiate agonists, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluconazole: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as fluconazole, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fentanyl is metabolized by CYP3A4 and concurrent use of inhibitors of this isoenzyme, such as fluoxetine, may increase the bioavailability of fentanyl leading to increased or prolonged effects such as respiratory depression. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
    Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fentanyl is metabolized by CYP3A4 and concurrent use of inhibitors of this isoenzyme, such as fluoxetine, may increase the bioavailability of fentanyl leading to increased or prolonged effects such as respiratory depression. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects. (Moderate) Concomitant use of fentanyl with other CNS depressants, such as olanzapine, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Fluphenazine: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as phenothiazines, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring are recommended to ensure the absence of hypotension and respiratory depression.
    Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If 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.
    Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fentanyl is metabolized by CYP3A4 and concurrent use of inhibitors of this isoenzyme, such as fluvoxamine, may increase the bioavailability of fentanyl leading to increased or prolonged effects such as respiratory depression. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
    Fosamprenavir: (Moderate) Fentanyl should be used with extreme caution if deemed appropriate for use in a patients taking fosamprenavir. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension. Fentanyl is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is an inducer of P-gp and a potent inhibitor and moderate inducer of CYP3A4.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Furosemide: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Gabapentin: (Moderate) Pain medications that contain opiate agonists may intensify CNS depressive adverse effects seen with gabapentin use, such as drowsiness or dizziness. Patients should limit activity until they are aware of how coadministration affects them.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and fentanyl as coadministration may increase serum concentrations of fentanyl and increase the risk of adverse effects. Fentanyl is a substrate of P-glycoprotein (P-gp); glecaprevir is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and fentanyl as coadministration may increase serum concentrations of fentanyl and increase the risk of adverse effects. Fentanyl is a substrate of P-glycoprotein (P-gp); pibrentasvir is a P-gp inhibitor.
    Glycerol Phenylbutyrate: (Moderate) Concomitant use of glycerol phenylbutyrate and fentanyl may result in decreased exposure of fentanyl. Fentanyl is a CYP3A substrate; glycerol phenylbutyrate is a weak inducer of CYP3A4. Monitor for decreased efficacy of fentanyl during coadministration.
    Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Glycopyrrolate; Formoterol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as fentanyl. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Grapefruit juice: (Moderate) Patients should avoid or limit their intake of grapefruit juice during fentanyl treatment. Fentanyl is metabolized by CYP3A4. Grapefruit juice may increase fentanyl concentrations and/or decrease systemic clearance by inhibiting CYP3A4, leading to increased or prolonged effects, including a risk for significant respiratory depression. If concomitant use is necessary, consider dosage reduction of fentanyl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Sudden discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl
    Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Guaifenesin; Phenylephrine: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as opiate agonists, when administered concomitantly.
    Guanfacine: (Moderate) Central-acting adrenergic agonists like guanfacine have CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Haloperidol: (Moderate) Concomitant use of fentanyl with other central nervous system (CNS) depressants, such as haloperidol, can potentiate the effects of fentanyl and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of fentanyl 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 fentanyl and/or haloperidol 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.
    Halothane: (Major) Concomitant use of fentanyl with other CNS depressants, such as general anesthetics, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hydantoins: (Major) Drugs that induce the hepatic cytochrome P450 3A4 isoenzyme, such as hydantoins, may induce fentanyl metabolism and thus, may decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed. Conversely, a downward dosage adjustment of fentanyl may be needed when a CYP3A4 inducer is stopped. Additive CNS depression could also be seen with the combined use of the hydantoin and opiate agonists.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydromorphone: (Major) Concomitant use of hydromorphone with other central nervous system (CNS) depressants, such as other opiate agonists, can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Ibrutinib: (Moderate) Use ibrutinib and fentanyl together with caution; plasma concentrations of fentanyl may increase resulting in increased toxicity. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; fentanyl is a P-gp substrate with a narrow therapeutic index.
    Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with fentanyl, a CYP3A substrate, as fentanyl toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Moderate) Concomitant use of iloperidone with other centrally-acting medications such as opiate agonists, may increase both the frequency and the intensity of adverse effects including drowsiness, sedation, and dizziness.
    Imatinib: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including fentanyl.
    Imipramine: (Moderate) Use caution in the use of fentanyl with tricyclic antidepressants (TCAs) because they can cause additive sedation, possible respiratory depression, or additive hypotension. Hypoventilation and profound sedation or hypotension may occur in severe cases. Additive effects on intestinal motility (constipation) or bladder function may also occur. Following the administration of fentanyl, the dose of other CNS depressant drugs should generally be reduced. If a patient is receiving fentanyl for chronic pain and the patient is taking a TCA, initiate fentanyl with care. Caution should also be observed when administering TCAs with opiates having serotonergic properties such as fentanyl. Serotonin syndrome may rarely occur and is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma). If serotonin syndrome is suspected, both the TCA and concurrent serotonergic agents should be discontinued.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Indapamide: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Indinavir: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as indinavir, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with fentanyl may result in increased serum concentrations of fentanyl. Fentanyl is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. Serotonin syndrome and death occurred in1 patient previously stable on the MAOI tranylcypromine following an uneventful CABG surgery in which fentanyl was administered. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl.
    Isoflurane: (Major) Concomitant use of fentanyl with other CNS depressants, such as general anesthetics, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of fentanyl. Dosages of fentanyl may need to be adjusted while the patient is receiving rifampin.
    Isoniazid, INH; Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of fentanyl. Dosages of fentanyl may need to be adjusted while the patient is receiving rifampin.
    Isradipine: (Moderate) Concomitant use of calcium channel blockers and fentanyl, especially in combination with beta- adrenergic blocking agents during surgical procedures, has resulted in severe hypotension. As is recommended with other calcium channel blockers, isradipine should be withheld for at least 36 hours, if possible, prior to the use of high-dose fentanyl.
    Itraconazole: (Major) Avoid use of fentanyl during and for 2 weeks after itraconazole therapy. Concomitant use may increase fentanyl plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of itraconazole could decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If itraconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for both CYP3A4 and P-glycoprotein (P-gp). Itraconazole is a potent inhibitor of CYP3A4 and an inhibitor of P-gp.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and fentanyl concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as fentanyl, can increase fentanyl exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Minor) Ixabepilone is a weak inhibitor of P-glycoprotein (Pgp). Fentanyl is a Pgp substrate, and concomitant use of ixabepilone with a Pgp substrate may cause an increase in fentanyl concentrations. Use caution if ixabepilone is coadministered with a Pgp substrate.
    Ketamine: (Major) Concomitant use of fentanyl with other CNS depressants, such as general anesthetics, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Ketoconazole: (Moderate) Ketoconazole may decrease the systemic clearance of fentanyl. Prolonged duration of opiate action, increased sedation, respiratory depression or other opiate side effects may occur. Close monitoring of patients is warranted.
    Labetalol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Lactobacillus: (Moderate) Concurrent use of antidiarrheals and opiate agonists, can lead to severe constipation and possibly additive CNS depression. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Lanreotide: (Moderate) Monitor for an increase in fentanyl-related adverse reactions such as respiratory depression and sedation if coadministration with lanreotide is necessary; consider reducing the dose of fentanyl if clinically appropriate. If lanreotide is discontinued, monitor for evidence of opioid withdrawal and consider increasing the fentanyl dose until stable drug effects are achieved. Coadministration with lanreotide can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lanreotide is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. Fentanyl is a CYP3A4 substrate. Limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of CYP3A4 substrates, which may be due to the suppression of growth hormone; it cannot be excluded that lanreotide has this effect.
    Lapatinib: (Moderate) Fentanyl is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and any CYP3A4 and/or P-glycoprotein substrate may lead to increased serum concentrations of the CYP3A4 and/or P-glycoprotein substrate. As increased serum concentrations are likely, cautious coadministration is recommended, and consider a dose reduction of the CYP3A4 and/or P-glycoprotein substrate.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of fentanyl-associated adverse reactions is advised with concomitant administration of ledipasvir. Fentanyl is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor. Taking these drugs together may increase fentanyl plasma concentrations.
    Levobetaxolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Levobunolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Levobupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Levocetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lincosamides: (Moderate) Lincosamides, which have been shown to exhibit neuromuscular blocking action, can enhance the effects of opiate agonists if used concomitantly, enhancing respiratory depressant effects. They should be used together with caution and the patient carefully monitored.
    Linezolid: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Linezolid is a reversible, non-selective inhibitor of MAO. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl.
    Lithium: (Major) There is an increased risk of serotonin syndrome during concurrent use of drugs with central serotonergic properties such as lithium and fentanyl. Signs and symptoms of serotonin syndrome include autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis, dizziness, hyperthermia), mental status changes (e.g., delirium, confusion, coma), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), gastrointestinal effects (e.g., nausea, vomiting, diarrhea), seizures, and in rare cases, death. If concurrent use is necessary, monitor for the emergence of serotonin syndrome and inform patients of the increased risk. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Loperamide: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Loperamide; Simethicone: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Lopinavir; Ritonavir: (Major) Concomitant use of fentanyl with CYP3A4 inhibitors, such as lopinavir; ritonavir, may increase fentanyl plasma concentrations and prolong opioid adverse reactions, which may lead to fatal respiratory depression. When using fentanyl with a CYP3A4 inhibitor, monitor patients closely at frequent intervals and consider a dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of the CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead a withdrawal syndrome in those with physical dependence to fentanyl. If the CYP3A4 inhibitor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. (Major) Use fentanyl in combination with ritonavir with extreme caution; ritonavir can significantly inhibit fentanyl's metabolism. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for signs of excessive fentanyl exposure such as oversedation, respiratory depression, and hypotension. Fentanyl is metabolized mainly by the cytochrome P450 (CYP) 3A4 isoenzyme and is a P-glycoprotein (P-gp) substrate. Ritonavir is a potent CYP3A4 inhibitor, and also inhibits P-gp. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%).
    Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    Loratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as opiate agonists. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may induce the metabolism of fentanyl, which could result in lack of therapeutic efficacy or the development of an abstinence syndrome in patients who are physically dependent on opioids. If coadministration is necessary, monitor the patient closely at frequent intervals for appropriate pain control and signs of opioid withdrawal. Consider fentanyl dosage adjustments until stable drug effects are achieved. If lumacaftor; ivacaftor is subsequently discontinued, fentanyl plasma concentrations will increase. Monitor the patient closely at frequent intervals for oversedation and respiratory depression and reduce the fentanyl dosage as appropriate. Fentanyl is a substrate of CYP3A4 and P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggestion lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of fentanyl through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (Moderate) Use caution when administering ivacaftor and fentanyl concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as fentanyl, can increase fentanyl exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may induce the metabolism of fentanyl, which could result in lack of therapeutic efficacy or the development of an abstinence syndrome in patients who are physically dependent on opioids. If coadministration is necessary, monitor the patient closely at frequent intervals for appropriate pain control and signs of opioid withdrawal. Consider fentanyl dosage adjustments until stable drug effects are achieved. If lumacaftor; ivacaftor is subsequently discontinued, fentanyl plasma concentrations will increase. Monitor the patient closely at frequent intervals for oversedation and respiratory depression and reduce the fentanyl dosage as appropriate. Fentanyl is a substrate of CYP3A4 and P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggestion lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of fentanyl through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as opiate agonists.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Moderate) Concomitant use of fentanyl with other central nervous system (CNS) depressants, such as maprotiline, 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 fentanyl 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 fentanyl and/or maprotiline 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.
    Mepenzolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Mephobarbital: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Mepivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mepivacaine; Levonordefrin: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for epidural analgesia or additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meprobamate: (Moderate) Concomitant use of fentanyl with meprobamate may cause respiratory depression, hypotension, and profound sedation. A coma could result in some circumstances. If concurrent use is desired, significantly reduce the dose of fentanyl and/or meprobamate. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable
    Mesoridazine: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as phenothiazines, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring are recommended to ensure the absence of hypotension and respiratory depression.
    Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of 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.
    Methadone: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methocarbamol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If 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.
    Methohexital: (Moderate) Drugs that induce the CYP3A4 isoenzyme, such as barbiturates, may induce fentanyl metabolism and decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed for those patients using these drugs chronically. Additive CNS and respiratory depression may be the more important issue during initial or acute use when barbiturates given with fentanyl. The combined use of CNS depressants like barbiturates with fentanyl can increase the risk of respiratory depression, hypotension, profound sedation, coma and death. Monitor for signs of respiratory depression, sedation, and hypotension. When considering combined therapy, the dose of one or both agents should be reduced.
    Methscopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl is used concomitantly with an anticholinergic drug. The concomitant use of fentanyl and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methyclothiazide: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly.
    Methylene Blue: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Methylene blue is a reversible inhibitor of MAO. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl.
    Metoclopramide: (Moderate) Opiate agonists antagonize GI motility and can decrease the gastroprokinetic effects of metoclopramide.
    Metolazone: (Moderate) Fentanyl may reduce the efficacy of diuretics due to induction of the release of antidiuretic hormone. Adjustments to diuretic therapy may be needed in some patients. In addition, opiate agonists may potentiate orthostatic hypotension when used concurrently with diuretics.
    Metoprolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Metreleptin: (Moderate) Carefully consider the risks and benefits of coadministration before giving metreleptin and fentanyl concomitantly; fentanyl dosage should be carefully selected and titrated. Upon initiation or discontinuation of metreleptin, carefully monitor patients for therapeutic and adverse effects of fentanyl and adjust the dosage as necessary. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as fentanyl.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as opiate agonists, should be used with caution. Additive drowsiness and/or dizziness is possible. Also, hydrocodone is metabolized by CYP3A4. Metyrapone, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with metyrapone.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
    Midazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mifepristone, RU-486: (Severe) Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum concentrations of drugs that are CYP3A4 substrates and that have a narrow therapeutic index, such as fentanyl. Coadministration is contraindicated when the drug is used chronically, such as in the treatment of Cushing's syndrome. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering milnacipran with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring is recommended during co-administration of fentanyl and milnacipran for signs and symptoms of serotonin syndrome or other serious effects.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Additive sedative effects may also occur. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Mirtazapine should be discontinued if a patient develops a combination of symptoms suggestive of serotonin syndrome.
    Mitotane: (Major) Use caution if mitotane and fentanyl are used concomitantly, and monitor for decreased efficacy of fentanyl and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and fentanyl is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of fentanyl. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with fentanyl.
    Mivacurium: (Major) Although adequate sedation and analgesia must accompany the use of neuromscular blockers, coadministration of opioids such as fentanyl may enhance neuromuscular blockade and produce an increased degree of respiratory depresssion. Monitor patients for signs of respiratory depression that may be greater than otherwise expected. A dose reduction of one or both drugs may be warranted.
    Molindone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as molindone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or molindone is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Monoamine oxidase inhibitors: (Major) The use of fentanyl is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days. Concomitant use of fentanyl with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. Serotonin syndrome and death occurred in1 patient previously stable on the MAOI tranylcypromine following an uneventful CABG surgery in which fentanyl was administered. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as fentanyl.
    Morphine: (Major) Concomitant use of morphine with fentanyl 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 fentanyl is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Morphine; Naltrexone: (Major) Concomitant use of morphine with fentanyl 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 fentanyl is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Nabilone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as nabilone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Nadolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Nalbuphine: (Major) Avoid the concomitant use of nalbuphine and opiate agonists, such as fentanyl. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists and reduce analgesic effects. Nalbuphine may cause withdrawal symptoms in patients receiving chronic opiate agonists. Concurrent use of nalbuphine 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: (Major) Naloxone is the pharmacologic opposite of fentanyl. Naloxone can block the actions of fentanyl and, if administered to patients who are dependent on fentanyl, can produce acute withdrawal and/or allow pain to recur.
    Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. 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.
    Nebivolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Nebivolol; Valsartan: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving beta-blockers. In addition, increased concentrations of fentanyl may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and fentanyl is a P-gp substrate. If these drugs are coadministered, the fentanyl dose may need to be very conservative, and the patient should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Nefazodone: (Moderate) Certain opiate agonists, such as fentanyl, are metabolized via cytochrome P450 3A4. Nefazodone inhibits the metabolism of these agents and may lead to excessive opiate agonist effects.
    Nelfinavir: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as nelfinavir, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
    Netupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fentanyl. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Neuromuscular blockers: (Major) Although adequate sedation and analgesia must accompany the use of neuromscular blockers, coadministration of opioids such as fentanyl may enhance neuromuscular blockade and produce an increased degree of respiratory depresssion. Monitor patients for signs of respiratory depression that may be greater than otherwise expected. A dose reduction of one or both drugs may be warranted.
    Nevirapine: (Moderate) Drugs that induce the hepatic cytochrome P450 3A4 isoenzyme, such as nevirapine, may induce fentanyl metabolism and thus, may decrease the effectiveness of fentanyl, a substrate of CYP3A4.
    Nicardipine: (Major) Concomitant use of fentanyl with CYP3A4 inhibitors, such as nicardipine, may increase fentanyl plasma concentrations and prolong opioid adverse reactions, which may lead to fatal respiratory depression. When using fentanyl with a CYP3A4 inhibitor, monitor patients closely at frequent intervals and consider a dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of the CYP3A4 inhibitor could decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead a withdrawal syndrome in those with physical dependence to fentanyl. If the CYP3A4 inhibitor is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. In addition, additive hypotensive effects may occur with coadministration. Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving a calcium channel blocker together with a beta-blocker and high dose fentanyl anesthesia. The possibility that a similar reaction may occur with only a calcium channel blocker and low dose fentanyl, or other opioids, cannot be ruled out. As is recommended with other calcium channel blockers, nicardipine should be withheld for at least 36 hours, if possible, prior to the use of high-dose fentanyl anesthesia.
    Nifedipine: (Moderate) Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine-treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.
    Nilotinib: (Major) Nilotinib is a substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp). Fentanyl is a substrate of CYP3A4 and P-gp and has a narrow therapeutic range. If these drugs are coadministered, the fentanyl dose may need to be very conservative; consider a fentanyl dose reduction. Patients should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Nimodipine: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Nisoldipine: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving calcium-channel blockers.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with opiate agonists.
    Nortriptyline: (Moderate) Use caution in the use of fentanyl with tricyclic antidepressants (TCAs) because they can cause additive sedation, possible respiratory depression, or additive hypotension. Hypoventilation and profound sedation or hypotension may occur in severe cases. Additive effects on intestinal motility (constipation) or bladder function may also occur. Following the administration of fentanyl, the dose of other CNS depressant drugs should generally be reduced. If a patient is receiving fentanyl for chronic pain and the patient is taking a TCA, initiate fentanyl with care. Caution should also be observed when administering TCAs with opiates having serotonergic properties such as fentanyl. Serotonin syndrome may rarely occur and is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma). If serotonin syndrome is suspected, both the TCA and concurrent serotonergic agents should be discontinued.
    Octreotide: (Moderate) Octreotide can cause additive constipation with opiate agonists such as fentanyl. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Monitor patients during concomitant use.
    Olanzapine: (Moderate) Concomitant use of fentanyl with other CNS depressants, such as olanzapine, may cause respiratory depression, hypotension, and profound sedation; a coma could result. If concurrent use of fentanyl and a CNS depressant is desired, significantly reduce the dose of fentanyl and/or the other CNS depressant. Blood pressure and respiration monitoring to ensure the absence of hypotension and respiratory depression, respectively may be desirable.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Use fentanyl in combination with ritonavir with extreme caution; ritonavir can significantly inhibit fentanyl's metabolism. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for signs of excessive fentanyl exposure such as oversedation, respiratory depression, and hypotension. Fentanyl is metabolized mainly by the cytochrome P450 (CYP) 3A4 isoenzyme and is a P-glycoprotein (P-gp) substrate. Ritonavir is a potent CYP3A4 inhibitor, and also inhibits P-gp. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%).
    Ondansetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as fentanyl. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Oritavancin: (Moderate) Fentanyl is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of fentanyl may be reduced if these drugs are administered concurrently. Induction of fentanyl metabolism may take several days. Dosages of fentanyl may require adjustment if oritavancin is initiated or withdrawn during fentanyl therapy.
    Orphenadrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an o