Pfizer Fentanyl Citrate Special Precautions

Hazardous and harmful use: Fentanyl contains the opioid fentanyl and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed fentanyl at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed fentanyl.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Abuse or intentional misuse of fentanyl may result in overdose and/or death. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Storage). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share fentanyl with anyone else.
Accidental ingestion/exposure: Accidental ingestion or exposure of fentanyl, especially by children, can result in a fatal overdose of fentanyl. Patients and their caregivers should be given information on safe storage and disposal of unused fentanyl (see Handling Instructions under Cautions for Usage and Storage).
Respiratory depression (hypoventilation): Profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the post-operative period. Hyperventilation during anesthesia may alter the patient's responses to CO2, thus affecting respiration post-operatively. Therefore, patients should remain under appropriate surveillance.
It has been reported that diminished sensitivity to CO2 stimulation may persist longer than depression of respiratory rate. This dose related effect of respiratory depression peaks between 5 and 15 minutes after injection, but seldom lasts longer than 30 minutes.
Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of fentanyl but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with existing impairment of respiratory function (e.g., chronic obstructive pulmonary disease, asthma) and in patients with hepatic and renal impairment (see Conditions which require dose reduction as follows). Opioids should be used with caution and with close monitoring in these patients (see Dosage & Administration). During anesthesia this may be managed by assisted or controlled respiration. The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
Respiratory depression caused by opioid analgesics is dose related and can be reversed by opioid antagonists, such as naloxone, but additional doses of naloxone may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist. Consult individual prescribing information (for naloxone) before employing opioid antagonists. Appropriate surveillance should be maintained for the duration of opioid antagonist action. The use of an opioid antagonist will also reverse analgesia. See also discussion of opioid antagonists in Overdosage.
Respiratory depression is more likely to occur with intravenous administration if a dose is given too rapidly and it rarely occurs with intramuscular administration.
Resuscitative equipment and an opioid antagonist should be readily available to manage apnea.
Opioids can cause central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.
The effect on respiratory depression persists longer than the measured analgesic effect, and care should be taken, with the total opioid dose considered when fentanyl is given postoperatively. The recommended dose may be as low as quarter of that normally prescribed.
Tolerance, dependence and withdrawal: Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid. Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g., naloxone) or partial agonist (e.g., buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing fentanyl in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids as follows and Dosage & Administration).
Ceasing opioids: Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal as previously mentioned). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualized plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Dosage & Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.
Head injuries and increased intracranial pressure: Fentanyl is contraindicated in patients who may be particularly susceptible to respiratory depression, such as comatose patients who may have a head injury or brain tumor (see Contraindications). In addition, fentanyl may obscure the clinical course of patients with a head injury.
The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients the transient decrease in the mean arterial pressure has occasionally been accompanied by a short-lasting reduction of the cerebral perfusion pressure.
Neonatal withdrawal syndrome: There is a risk that newborn infants will experience neonatal withdrawal syndrome following prolonged used of opioids, including fentanyl, during pregnancy (see Use in pregnancy under Use in Pregnancy & Lactation).
Hyperalgesia: Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal as previously mentioned). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.
Severe cardiovascular depression: Fentanyl may cause severe bradycardia, severe hypotension including orthostatic hypotension, and syncope. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see Interactions). In patients with circulatory shock, fentanyl may cause vasodilation that can further reduce cardiac output and blood pressure. Monitor these patients for signs of hypotension after initiating or titrating the dosage of fentanyl.
Cardiac effects: Fentanyl should be used with caution in patients with cardiac arrhythmias, including bradyarrhythmia (due to its weak cholinergic activity). Fentanyl may produce bradycardia, and possibly asystole, if the patient has received an insufficient amount of anticholinergic, or when fentanyl is combined with non-vagolytic muscle relaxants. Opioids may induce hypotension, particularly in hypovolemic patients. Appropriate measures should be taken to maintain stable arterial pressure.
Muscle rigidity: Intravenous administration of fentanyl may cause muscle rigidity, particularly of the muscles of respiration and alter the rate of respiration especially in patients suffering from myasthenia gravis. This effect is related to the speed of injection and its incidence can be reduced by a slow intravenous injection (ordinarily sufficient for lower doses) and the use of muscle relaxants.
Non-epileptic myoclonic movements can occur.
Conditions which require dose reduction: Dosage reduction is desirable in patients suffering from hypothyroidism, chronic hepatic disease, pulmonary disease, decreased respiratory reserve and alcoholism. Such patients also require prolonged post-operative monitoring.
Management of complications: Patients receiving fentanyl should be kept under close medical supervision. Resuscitative facilities and an opioid antagonist compatible with the patient's condition should be available for the management of complications.
Fentanyl as a supplement for anesthesia: Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics can alter respiration by blocking intercostal nerves. Through other mechanisms, fentanyl can also alter respiration. Therefore, when fentanyl is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved and be prepared to manage them in patients selected for these forms of anesthesia.
Supervision during use: Fentanyl should only be used by experienced physicians and in patients who are under constant supervision.
Serotonin syndrome: Caution is advised when fentanyl is co-administered with drugs that affect the serotonergic neurotransmitter systems. The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs), Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.
Serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
If serotonin syndrome is suspected, rapid discontinuation of fentanyl should be considered.
Cytochrome P450 3A4 interactions: Concomitant use of fentanyl with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may exacerbate respiratory depression (see information as follows), particularly when an inhibitor is added after a stable dose of fentanyl is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in fentanyl-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using fentanyl with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in fentanyl-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl (see Dosage & Administration and Interactions).
Concomitant use of fentanyl with CYP3A4 inducers, or discontinuation of a CYP3A4 inhibitor, could result in lower than expected fentanyl plasma concentrations and decrease efficacy. When using fentanyl with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor, monitor patients closely at frequent intervals and consider adjusting the fentanyl dosage (see Dosage & Administration and Interactions).
Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol: Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of fentanyl with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics, general anesthetics, tranquilizers, or other CNS depressants, including alcohol, should be reserved for patients for whom other treatment options are not possible.
If a decision is made to prescribe fentanyl concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.
Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking fentanyl.
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Interactions).
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of medicine-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Interactions).
Combination with neuroleptics: When fentanyl is used in conjunction with neuroleptics such as droperidol, the differing duration of action should be taken into account. Hypotension can occur which may be due to hypovolemia so appropriate parenteral therapy should be readily available.
General: As has been observed with all opioid analgesics, episodes suggestive of sphincter of Oddi spasm may occur with fentanyl.
Vital signs should be monitored carefully.
Obese Patients: Fentanyl should be administered with additional caution in obese patients. Obese patients should be observed carefully for signs of fentanyl toxicity.
Use in hepatic impairment: Fentanyl should be administered with caution to patients with liver dysfunction.
Use in renal impairment: Fentanyl should be administered with caution to patients with kidney dysfunction. They should be observed carefully for signs of fentanyl toxicity. Such patients also require prolonged post-operative monitoring.
Effects on laboratory tests: No data available.
Effects on Ability to Drive and Use Machines: Fentanyl may cause drowsiness and general impairment of co-ordination and may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. Ambulatory patients should be cautioned against driving or operating machinery. Patients should only drive or operate a machine if sufficient time has elapsed (at least 24 hours) after the administration of fentanyl.
Use in Children: Safe use of fentanyl in children younger than 2 years has not been established. It should not be administered in children younger than 2 years of age.
Use in the elderly or debilitated patient: Elderly patients may require lower doses of fentanyl and a varied dosage regimen as they may be more susceptible to adverse effects, such as respiratory depression and cardiovascular effects. They may also have age-related kidney function impairment, resulting in lower clearance rates of fentanyl.