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.
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.
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.
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 more than 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.
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: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
Acetaminophen; Butalbital; Caffeine: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
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) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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. (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.
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) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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.
Amlodipine; Atorvastatin: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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.
Amlodipine; Benazepril: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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.
Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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. (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.
Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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. (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.
Amlodipine; Olmesartan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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.
Amlodipine; Telmisartan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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.
Amlodipine; Valsartan: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine 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 amlodipine 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.
Amobarbital: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
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.
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.
Apalutamide: (Major) Monitor for reduced efficacy of fentanyl and signs of opioid withdrawal if coadministration with apalutamide is necessary; consider increasing the dose of fentanyl as needed. If apalutamide is discontinued, consider a dose reduction of fentanyl and frequently monitor for signs or respiratory depression and sedation. Fentanyl is a CYP3A4 substrate and apalutamide 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.
Apomorphine: (Major) Concomitant use of opiate agonists with apomorphine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with apomorphine 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 apomorphine, use a lower initial dose of the opiate and titrate to clinical response. If apomorphine is prescribed for a patient taking an opiate agonist, use a lower initial dose of apomorphine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
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: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
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: (Moderate) Although adequate sedation and analgesia must accompany the use of neuromuscular blockers, coadministration of opioids such as fentanyl, may enhance neuromuscular blockade and produce an increased degree of respiratory depression, hypotension, or sedation. Monitor patients for signs of respiratory depression or sedation that may be greater than otherwise expected. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
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: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of 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.
Azelastine: (Major) Concomitant use of opiate agonists with azelastine nasal spray may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking azelastine nasal spray, use a lower initial dose of the opiate and titrate to clinical response. If azelastine is prescribed for a patient taking an opiate agonist, use a lower initial dose of azelastine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Use of azelastine ophthalmic solution with fentanyl would not be expected to increase the risk of CNS or respiratory depression.
Azelastine; Fluticasone: (Major) Concomitant use of opiate agonists with azelastine nasal spray may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking azelastine nasal spray, use a lower initial dose of the opiate and titrate to clinical response. If azelastine is prescribed for a patient taking an opiate agonist, use a lower initial dose of azelastine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Use of azelastine ophthalmic solution with fentanyl would not be expected to increase the risk of CNS or respiratory depression.
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.
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: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of 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.
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: (Major) Concurrent use of opioid agonists with barbiturates may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with barbiturates to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If an opioid agonist is initiated in a patient taking a barbiturate, reduce initial dosage and titrate to clinical response. If a barbiturate is prescribed in a patient taking an opioid agonist, use a lower initial dose of the barbiturate and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Additionally, concurrent use of fentanyl with barbiturates may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. Monitor for signs of opioid withdrawal. Discontinuation of barbiturates may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Barbiturates are inducers of CYP3A4, an isoenzyme responsible for the metabolism of fentanyl.
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: (Minor) Monitor for an increase in fentanyl-related adverse reactions, including sedation and respiratory depression, if coadministration with cabozantinib is necessary. Fentanyl is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, 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) Monitor for reduced efficacy of fentanyl and signs of opioid withdrawal if coadministration with carbamazepine is necessary; consider increasing the dose of fentanyl as needed. If carbamazepine is discontinued, consider a dose reduction of fentanyl and frequently monitor for signs or respiratory depression and sedation. Fentanyl is a CYP3A4 substrate and carbamazepine 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.
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) Concurrent use of fentanyl with cimetidine 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 cimetidine 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 cimetidine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate of CYP3A4, and cimetidine is an inhibitor of CYP3A4.
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: (Moderate) Although adequate sedation and analgesia must accompany the use of neuromuscular blockers, coadministration of opioids such as fentanyl, may enhance neuromuscular blockade and produce an increased degree of respiratory depression, hypotension, or sedation. Monitor patients for signs of respiratory depression or sedation that may be greater than otherwise expected. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
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.
Clevidipine: (Moderate) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with clevidipne. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving clevidipine.
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.
Clopidogrel: (Moderate) Coadministration of opioid agonists delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If 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) Concurrent use of fentanyl with dalfopristin; quinupristin 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 dalfopristin; quinupristin 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 dalfopristin; quinupristin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for CYP3A4, and dalfopristin; quinupristin is an inhibitor of CYP3A4.
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 darifenacin, an anticholinergic drug for overactive bladder. is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (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%).
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.
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, caution should be observed when coadministering drugs that have serotonergic properties such as desvenlafaxine and 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. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
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: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of diltiazem is necessary. If diltiazem is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a sensitive CYP3A4 substrate, and coadministration with a CYP3A4 inhibitor like diltiazem 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 diltiazem 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.
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: (Moderate) Although adequate sedation and analgesia must accompany the use of neuromuscular blockers, coadministration of opioids such as fentanyl, may enhance neuromuscular blockade and produce an increased degree of respiratory depression, hypotension, or sedation. Monitor patients for signs of respiratory depression or sedation that may be greater than otherwise expected. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
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.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (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. Closely monitor for increased side effects if these drugs are administered together.
Enalapril; Felodipine: (Moderate) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with felodipine. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving felodipine.
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) Monitor patients for bradycardia and hypotension when fentanyl is coadministered with felodipine. Fentanyl may cause bradycardia. The risk of significant hypotension and/or bradycardia during therapy with fentanyl is increased in patients receiving felodipine.
Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fesoterodine, an anticholinergic drug for overactive bladder. is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
Flavoxate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when 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.
Fostamatinib: (Moderate) Monitor for fentanyl toxicities that may require fentanyl dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 or P-gp substrate may increase the concentration of the CYP3A4 or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; fentanyl is a substrate for CYP3A4 and P-gp. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
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) Concurrent use of fentanyl with imatinib 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 imatinib 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 imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for CYP3A4, and imatinib is an inhibitor of CYP3A4.
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 b