fentanyl citrate injection, USP VIAL , AMPULE

2.1 Important Dosage and Administration Instructions

Fentanyl Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.

•

Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available.

•

Individualize dosage based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.

•

Monitor vital signs routinely.

As with other potent opioids, the respiratory depressant effect of fentanyl may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

If Fentanyl Citrate Injection is administered with a CNS depressant, become familiar with the properties of each drug, particularly each product's duration of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available [see Warnings and Precautions (5.3)].

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Dosage

50 mcg = 0.05 mg = 1 mL

5.1 Addiction, Abuse, and Misuse

Fentanyl Citrate Injection contains fentanyl, a Schedule CII controlled substance. As an opioid, Fentanyl Citrate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Opioids are sought for nonmedical use and are subject to diversion from ‎legitimate prescribed use. Consider these risks when handling Fentanyl Citrate Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Fentanyl Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential [see Dosage and Administration (2)]. As with other potent opioids, the respiratory depressant effect of fentanyl may persist longer that the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics, can alter respiration by blocking intercostal nerves. Through other mechanisms [see Clinical Pharmacology (12.2)] Fentanyl Citrate Injection can also alter respiration. Therefore, when Fentanyl Citrate Injection 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 the patients selected for these forms of anesthesia.

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Fentanyl Citrate Injection. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression.

Monitor such patients closely including vital signs, particularly when initiating and titrating Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential [see Dosage and Administration (2)].

Opioids can cause sleep-related breathing disorders including 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 [see Dosage and Administration (2.1)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other Central Nervous System Depressants

When benzodiazepines or other CNS depressants are used with Fentanyl Citrate Injection, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of Fentanyl Citrate Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When Fentanyl Citrate Injection is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Fentanyl Citrate Injection with benzodiazepines and/or other CNS depressants‎, including alcohol‎ (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-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 Drug Interactions (7)].

If the decision is made to manage postoperative pain with Fentanyl Citrate Injection concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available. [see Drug Interactions (7)].

5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Fentanyl Citrate Injection 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 Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Fentanyl Citrate Injection-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using Fentanyl Citrate Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Fentanyl Citrate Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Fentanyl Citrate Injection [see Dosage and Administration (2.1), Drug Interactions (7)].

Concomitant use of Fentanyl Citrate Injection with CYP3A4 inducers, or discontinuation of a CYP3A4 inhibitor, could result in lower than expected fentanyl plasma concentrations, decreased efficacy, or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using Fentanyl Citrate Injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor, monitor patients closely at frequent intervals and consider increasing the fentanyl dosage. [see Dosage and Administration (2.1), Drug Interactions (7)].

5.5 Risks of Muscle Rigidity and Skeletal Muscle Movement

Fentanyl Citrate Injection may cause muscle rigidity, particularly involving the muscles of respiration. The incidence and severity of muscle rigidity is dose related. These effects are related to the dose and speed of injection. Skeletal muscle rigidity also has been reported to occur or recur infrequently in the extended postoperative period usually following high dose administration. In addition, skeletal muscle movements of various groups in the extremities, neck, and external eye have been reported during induction of anesthesia with Fentanyl Citrate Injection; these reported movements have, on rare occasions, been strong enough to pose patient management problems.

These effects are related to the dose and speed of injection and its incidence can be reduced by: 1) administration of up to 1/4 of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent just prior to administration of Fentanyl Citrate Injection; 2) administration of a full paralyzing dose of a neuromuscular blocking agent following loss of eyelash reflex when Fentanyl Citrate Injection is used in anesthetic doses titrated by slow intravenous infusion; or, 3) simultaneous administration of Fentanyl Citrate Injection and a full paralyzing dose of a neuromuscular blocking agent when Fentanyl Citrate Injection is used in rapidly administered anesthetic dosages. The neuromuscular blocking agent used should be compatible with the patient's cardiovascular status.

5.6 Severe Cardiovascular Depression

Fentanyl Citrate Injection 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 Drug Interactions (7)]. In patients with circulatory shock, Fentanyl Citrate Injection 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 Citrate Injection.

5.7 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic ‎paradoxically causes an increase in pain, or an increase in sensitivity to pain. ‎This condition differs from tolerance, which is the need for increasing doses of ‎opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH ‎include (but may not be limited to) increased levels of pain upon opioid dosage ‎increase, decreased levels of pain upon opioid dosage decrease, or pain from ‎ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only ‎if there is no evidence of underlying disease progression, opioid tolerance, ‎opioid withdrawal, or addictive behavior.‎

Cases of OIH have been reported, both with short-term and longer-term use of ‎opioid analgesics. Though the mechanism of OIH is not fully understood, ‎multiple biochemical pathways have been implicated. Medical literature suggests ‎a strong biologic plausibility between opioid analgesics and OIH and allodynia. If ‎a patient is suspected to be experiencing OIH, carefully consider appropriately ‎decreasing the dose of the current opioid analgesic or opioid rotation (safely ‎switching the patient to a different opioid moiety) [see Dosage and ‎Administration (2), Warnings and Precautions (5.7)].‎

5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of fentanyl with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.

5.9 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Fentanyl Citrate Injection may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for worsening of signs of increasing intracranial pressure. Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy with Fentanyl Citrate Injection.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Fentanyl Citrate Injection in patients with impaired consciousness or coma.

5.11 Risks of Use in Patients with Gastrointestinal Conditions

Fentanyl may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.12 Increased Risk of Seizures in Patients with Seizure Disorders

Fentanyl may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Fentanyl Citrate Injection therapy.

5.13 Risks of Driving and Operating Machinery

Fentanyl may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery after Fentanyl Citrate Injection administration.

5.14 Risks due to Interaction with Neuroleptic Agents

Many neuroleptic agents have been associated with QT prolongation, torsades de pointes, and cardiac arrest. Administer neuroleptic agents with extreme caution in the presence of risk factors for development of prolonged QT syndrome and torsades de pointes, such as: 1) clinically significant bradycardia (less than 50 bpm), 2) any clinically significant cardiac disease, including baseline prolonged QT interval, 3) treatment with Class 1 and Class III antiarrhythmics, 4) treatment with monoamine oxidase inhibitors (MAOI's), 5) concomitant treatment with other drug products known to prolong the QT interval and 6) electrolyte imbalance, in particular hypokalemia and hypomagnesemia, or concomitant treatment with drugs (e.g., diuretics) that may cause electrolyte imbalance.

Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia.

ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.

When Fentanyl Citrate Injection is used with a neuroleptic and an EEG is used for postoperative monitoring, the EEG pattern may return to normal slowly.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of Fentanyl Citrate Injection in children under two years of age has not been established.

Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included the combined use of fentanyl, pancuronium and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to fentanyl. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Fentanyl Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)].

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Hepatic Impairment

Fentanyl Citrate Injection should be administered with caution to patients with liver dysfunction because of the extensive hepatic metabolism. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

8.7 Renal Impairment

Fentanyl Citrate Injection should be administered with caution to patients with kidney dysfunction because of the renal excretion of fentanyl and its metabolites. Reduce the dosage as needed and monitor for signs of respiratory depression, sedation, and hypotension.

9.1 Controlled Substance

Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled substance.

9.2 Abuse

Fentanyl Citrate Injection contains fentanyl, a substance with high potential for misuse and abuse, which can lead to the development of ‎substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an ‎individual in a way other than prescribed by a healthcare provider or for ‎whom it was not prescribed.‎

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful ‎consequences, giving a higher priority to drug use than other activities and ‎obligations), and possible tolerance or physical dependence.‎

Misuse and abuse of Fentanyl Citrate Injection increases risk of ‎overdose, which may lead to central nervous system and respiratory ‎depression, hypotension, seizures, and death. The risk is increased with ‎concurrent abuse of Fentanyl Citrate Injection with alcohol and/or other ‎CNS depressants. Abuse of and addiction to opioids in ‎some individuals may not be accompanied by concurrent tolerance and ‎symptoms of physical dependence. In addition, abuse of opioids can ‎occur in the absence of addiction.‎

All patients treated with opioids require careful and frequent reevaluation ‎for signs of misuse, abuse, and addiction, because use of opioid analgesic ‎products carries the risk of addiction even under appropriate medical use. ‎Patients at high risk of Fentanyl Citrate Injection abuse include those with ‎a history of prolonged use of any opioid, including products containing fentanyl, those with a ‎history of drug or alcohol abuse, or those who use Fentanyl Citrate ‎Injection in combination with other abused drugs.‎

‎“Drug-seeking” behavior is very common in persons with substance use ‎disorders. Drug-seeking tactics include emergency calls or visits near the ‎end of office hours, refusal to undergo appropriate examination, testing, or ‎referral, repeated “loss” of prescriptions, tampering with prescriptions, ‎and reluctance to provide prior medical records or contact information for ‎other treating healthcare provider(s). “Doctor shopping” (visiting multiple ‎prescribers to obtain additional prescriptions) is common among people ‎who abuse drugs and people with substance use disorder. Preoccupation ‎with achieving adequate pain relief can be appropriate behavior in a ‎patient with inadequate pain control.‎

Fentanyl Citrate Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

9.3 Dependence

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to ‎a drug after repeated administration (i.e., a higher dose of a drug is ‎required to produce the same effect that was once obtained at a lower ‎dose).‎

Physical dependence is a state that develops as a result of a ‎physiological adaptation in response to repeated drug use, manifested by ‎withdrawal signs and symptoms after abrupt discontinuation or a ‎significant dose reduction of a drug.‎

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Fentanyl Citrate Injection should not be abruptly discontinued in a ‎physically-dependent patient. If Fentanyl Citrate Injection is abruptly ‎discontinued in a physically-dependent patient, a withdrawal syndrome ‎may occur, typically characterized by restlessness, lacrimation, rhinorrhea, ‎perspiration, chills, myalgia, and mydriasis. Other signs and symptoms ‎also may develop, including irritability, anxiety, backache, joint pain, ‎weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, ‎diarrhea, or increased blood pressure, respiratory rate, or heart rate.‎

Infants born to mothers physically-dependent on opioids will also be ‎physically-dependent and may exhibit respiratory difficulties and ‎withdrawal signs [see Use in Specific Populations (8.1)].‎

Clinical Presentation

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentanyl Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.

In an individual physically-dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically-dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

12.1 Mechanism of Action

Fentanyl is an opioid agonist whose principal actions of therapeutic value are analgesic and sedation.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Fentanyl Citrate Injection is administered by the intravenous or intramuscular route. The pharmacokinetics of fentanyl can be described as a three-compartment model.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Protect from light. Retain in carton until time of use.

Store at 20°C to 25°C (68°F to 77°F). [see USP Controlled Room Temperature.]

Addiction, Abuse, and Misuse ‎

Inform patients that the use of Fentanyl Citrate Injection, even when taken as recommended, can result in ‎addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. ‎

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is ‎greatest when starting Fentanyl Citrate Injection or when the dosage is increased, and that it can occur ‎even at recommended dosages ‎[see Warnings and Precautions (5.2)]‎.‎

Hyperalgesia and Allodynia

Advise ‎patients to inform their healthcare provider if they ‎experience symptoms of hyperalgesia, including worsening ‎pain, increased ‎sensitivity to pain, or new pain [see Warnings and Precautions (5.7), ‎Adverse Reactions (6)].‎

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if ‎symptoms develop after discharge from the hospital.‎ Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.8), Drug Interactions (7)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Clinical Pharmacology (12.2)].