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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, and Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.2 ) • Risks of Muscle Rigidity and Skeletal Muscle Movement : Manage with neuromuscular blocking agent. See full prescribing information for more detail on managing these risks. ( 5.5 ) • 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. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.6 ) • Serotonin Syndrome : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue Alfentanil Injection if serotonin syndrome is suspected. ( 5.7 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, and Head Injury : Monitor for sedation and respiratory depression. ( 5.10 ) 5.1 Addiction, Abuse, and Misuse Alfentanil Injection contains alfentanil, a Schedule II controlled substance. As an opioid, Alfentanil 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 Alfentanil Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug . Contact local and 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. Alfentanil Injection should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Alfentanil 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 (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. As with other potent opioids, the respiratory depressant effect of Alfentanil Injection 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. Certain forms of conduction anesthesia, such as spinal anesthesia and some epidural anesthetics, can alter respiration by blocking intercostal nerves [see Clinical Pharmacology (12.2) ] . Alfentanil Injection can also alter respiration. Therefore, when Alfentanil 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 Alfentanil 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 Alfentanil Injection and when Alfentanil Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Alfentanil 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 CNS Depressants When benzodiazepines or other CNS depressants are used with Alfentanil 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 Alfentanil Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression. When Alfentanil 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 [see Drug Interactions (7) ] . Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Alfentanil Injection with benzodiazepines and/or other CNS depressants including alcohol (e.g., nonbenzodiazepine 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 Alfentanil 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 Alfentanil 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 Alfentanil Injection and prolong opioid adverse reactions, which may exacerbate fatal respiratory depression [see Warnings and Precautions (5.5) ] , particularly when an inhibitor is added after a stable dose of Alfentanil Injection is achieved . Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Alfentanil Injection-treated patients may increase alfentanil plasma concentrations and prolong opioid adverse reactions. When using Alfentanil Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Alfentanil Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Alfentanil Injection [see Dosage and Administration (2.1) , Drug Interactions (7) ]. Concomitant use of Alfentanil Injection with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could result in lower than expected alfentanil plasma concentrations, and decrease efficacy, or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to alfentanil. When using Alfentanil Injection with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing Alfentanil Injection dosage [see Dosage and Administration (2.1) , Drug Interactions (7) ] . 5.5 Risks of Muscle Rigidity and Skeletal Muscle Movement Alfentanil Injection administered in initial dosages up to 20 mcg/kg may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is usually dose-related. Administration of Alfentanil Injection at anesthetic induction dosages (above 130 mcg/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids. Alfentanil may produce muscular rigidity that involves all skeletal muscles, including those of the neck and extremities. The incidence may be reduced by: 1) routine methods of administration of neuromuscular blocking agents for balanced opioid anesthesia; 2) administration of up to 1/4 of the full paralyzing dose of a neuromuscular blocking agent just prior to administration of Alfentanil Injection at dosages up to 130 mcg/kg; following loss of consciousness, a full paralyzing dose of a neuromuscular blocking agent should be administered; or 3) simultaneous administration of Alfentanil Injection and a full paralyzing dose of a neuromuscular blocking agent when Alfentanil Injection is used in rapidly administered anesthetic dosages (above 130 mcg/kg). The neuromuscular blocking agent used should be appropriate for the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered Alfentanil Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Patients receiving monitored anesthesia care (MAC) should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure; oxygen supplementation should be immediately available and provided where clinically indicated; oxygen saturation should be continuously monitored; the patient should be observed for early signs of hypotension, apnea, upper airway obstruction and/or oxygen desaturation. 5.6 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 (5.2) ] . 5.7 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Alfentanil Injection 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 Alfentanil Injection if serotonin syndrome is suspected. 5.8 Potentiation of Monoamine Oxidase Inhibitors Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported rarely with alfentanil. Therefore when Alfentanil Injection is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is recommended. 5.9 Bradycardia Alfentanil can cause bradycardia. Severe bradycardia and asystole have been successfully treated with atropine and conventional resuscitative methods. Monitor patients closely while receiving Alfentanil Injection have atropine and other resuscitative equipment present. 5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Alfentanil Injection may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Alfentanil Injection increasing intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. 5.11 Risks of Use in Patients with Gastrointestinal Conditions Alfentanil 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 Alfentanil 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 Alfentanil Injection therapy. 5.13 Risks of Driving and Operating Machinery Alfentanil Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery after Alfentanil Injection administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Alfentanil Injection and know how they will react to the medication. 5.14 Risks due to Hypersensitivity Reactions Alfentanil Injection may cause anaphylaxis reactions. Care should be exercised when administering to patients with known hypersensitivity to alfentanil or other opioid analgesics.