2.1 Important Dosage and Administration Instructions

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

In patients administered high doses of Alfentanil HCl Injection, it is essential that qualified personnel and adequate facilities are available for the management of postoperative respiratory depression.

• 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.
• The selection of preanesthetic medications should be based upon the needs of the individual patient.
• The neuromuscular blocking agent selected should be compatible with the patient's condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required.
• 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.
• Delayed respiratory depression, respiratory arrest, bradycardia, asystole, arrhythmias and hypotension have also been reported. Therefore, vital signs must be monitored continuously, including following the termination of surgery.
• Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
• For purposes of administering small volumes of Alfentanil HCl Injection accurately, the use of a tuberculin syringe or equivalent is recommended.

As with other potent opioids, the respiratory depressant effect of alfentanil 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 Alfentanil HCl 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 (5.5)].

The physical and chemical compatibility of Alfentanil HCl Injection have been demonstrated in solution with normal saline, 5% dextrose in normal saline, 5% dextrose in water and Lactated Ringers. Clinical studies of Alfentanil HCl Injection infusion have been conducted with Alfentanil HCl Injection diluted to a concentration range of 25 mcg/mL to 80 mcg/mL.

As an example of the preparation of Alfentanil HCl Injection for infusion, 20 mL of Alfentanil HCl injection added to 230 mL of diluent provides 40 mcg/mL solution of Alfentanil.

2.2 Dosage

The dosage of Alfentanil HCl Injection should be individualized and titrated to the desired effect in each patient according to body weight, physical status, underlying pathological condition, use of other drugs, and type and duration of surgical procedure and anesthesia. The dose of Alfentanil HCl Injection should be reduced in elderly or debilitated patients [see Warnings and Precautions (5.6)].

See Dosing Chart for the use of Alfentanil HCl Injection

1. by incremental injection as an analgesic adjunct to anesthesia with barbiturate/nitrous oxide/oxygen for short surgical procedures (expected duration of less than one hour);
2. by continuous infusion as a maintenance analgesic with nitrous oxide/oxygen for general surgical procedures; and
3. by intravenous injection in anesthetic doses for the induction of anesthesia for general surgical procedures with a minimum expected duration of 45 minutes; and
4. by intravenous injection as the analgesic component for monitored anesthesia care (MAC).

When administering Alfentanil as induction doses, administer the dose slowly (over three minutes). Because administration of the induction dose may produce loss of vascular tone and hypotension, consider given to fluid replacement prior to induction.

2.3 Discontinuation of Alfentanil HCl Injection

Alfentanil HCl Injection infusions should be discontinued at least 10 to 15 minutes prior to the end of surgery during general anesthesia. During administration of Alfentanil HCl Injection for Monitored Anesthesia Care (MAC), infusions may be continued to the end of the procedure.

2.4 Dosage Modification in Elderly Patients

Reduce the initial dose of Alfentanil HCl Injection in elderly patients by up to 40% due to reduced clearance and increased sensitivity to the effects. [see Specific Populations (8.5)]. The effect of the initial dose should be considered in determining supplemental doses.

2.5 Dosage Modifications in Obese Patients

In obese patients (more than 20% above ideal body weight) the dose of Alfentanil HCl Injection should be determined on the basis of lean body weight.

2.6 Dosage Modifications with Concomitant Use with Other CNS Depressants

Other CNS depressant drugs (e.g. barbiturates, tranquilizers, narcotics and general anesthetics) will have additive or potentiating effects with Alfentanil HCl Injection. When patients have received such drugs, the dose of Alfentanil HCl Injection, required will be less than usual. Following the administration of Alfentanil HCl Injection, the dose of other CNS depressant drugs should be reduced. [see Drug Interactions (7)].

5.1 Addiction, Abuse, and Misuse

Alfentanil HCl Injection contains alfentanil, a Schedule II controlled substance. As an opioid, Alfentanil HCl Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling Alfentanil HCl 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 HCl 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 HCl 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.

As with other potent opioids, the respiratory depressant effect of Alfentanil HCl 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 HCl Injection can also alter respiration. Therefore, when Alfentanil HCl 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 HCl 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 HCl Injection and when Alfentanil HCl Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Alfentanil HCl 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 of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Alfentanil HCl 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 HCl Injection and prolong opioid adverse reactions, which may exacerbate fatal respiratory depression [see Warnings and Precautions (5.4)], particularly when an inhibitor is added after a stable dose of Alfentanil HCl Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Alfentanil HCl Injection-treated patients may increase alfentanil plasma concentrations and prolong opioid adverse reactions. When using Alfentanil HCl Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Alfentanil HCl Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Alfentanil HCl Injection [see Dosage and Administration (2.1), Drug Interactions (7)].

Concomitant use of Alfentanil HCl Injection with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could result in lower than expected alfentanil plasma concentrations, and decrease efficacy. When using Alfentanil HCl Injection with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing Alfentanil HCl Injection dosage [see Dosage and Administration (2.1), Drug Interactions (7)].

5.4 Risks of Muscle Rigidity and Skeletal Muscle Movement

Alfentanil HCl 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 HCl 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 HCl 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 HCl Injection and a full paralyzing dose of a neuromuscular blocking agent when Alfentanil HCl 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 HCl 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.

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

When Alfentanil HCl 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)].

5.6 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 HCl 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). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Alfentanil HCl Injection if serotonin syndrome is suspected.

5.7 Potentiation of Monoamine Oxidase Inhibitors

Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported rarely with alfentanil. Therefore when Alfentanil HCl 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.

5.8 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 HCl Injection had have atropine and other resuscitative equipment present.

5.9 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 CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Alfentanil HCl Injection may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of increasing intracranial pressure.

5.10 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.

5.11 Increased Risk of Seizures in Patients with Convulsive or 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 HCl Injection therapy.

5.12 Risks due to Hypersensitivity Reactions

Alfentanil HCl Injection may cause anaphylaxis reactions. Care should be exercised when administering to patients with known hypersensitivity to alfentanil or other opioid analgesics.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reaction information is derived from controlled and open clinical trials in 785 patients who received intravenous Alfentanil HCl Injection during induction and maintenance of general anesthesia. The controlled trials included treatment comparisons with fentanyl, thiopental sodium, enflurane, saline placebo and halothane. The incidence of certain side effects is influenced by the type of use, e.g., chest wall rigidity has a higher reported incidence in clinical trials of Alfentanil HCl Injection induction, and by the type of surgery, e.g., nausea and vomiting have a higher reported incidence in patients undergoing gynecologic surgery. The overall reports of nausea and vomiting with alfentanil were comparable to fentanyl.

Incidence Greater than 1% - Probably Causally Related (Derived from clinical trials)

Gastrointestinal: Nausea (28%), vomiting (18%)

Cardiovascular: Arrhythmia, bradycardia (14%), hypertension (18%), hypotension (10%), tachycardia (12%)

Musculoskeletal: Chest wall rigidity (17%), skeletal muscle movements*

Respiratory: Apnea*, postoperative respiratory depression

Central Nervous System: Blurred vision, dizziness*, sleepiness/postoperative sedation

*Incidence 3% to 9%; all others 1% to 3%

Incidence Less than 1% - Probably Causally Related (Derived from clinical trials)

Adverse events reported in post-marketing surveillance, not seen in clinical trials, are italicized.

Body as a whole: Anaphylaxis

Central Nervous System: Headache*, myoclonic movements, postoperative confusion*, postoperative euphoria*, shivering*

Dermatological: Itching*, urticaria*

Injection Site: Pain*

Musculoskeletal: Skeletal muscle rigidity of neck and extremities

Respiratory: Bronchospasm, hypercarbia*, laryngospasm*

*Incidence 0.3% to 1%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of alfentanil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Adequate data to support the use of Alfentanil HCl Injection in children under the age of 12 years of age are not presently available.

8.5 Geriatric Use

In one clinical trial, the dose of alfentanil required to produce anesthesia, as determined by appearance of delta waves in EEG, was 40% lower in geriatric patients than that needed in healthy young patients.

The initial dose of Alfentanil HCl Injection should be appropriately reduced in elderly. Patients over the age of 65 have been found to have reduced plasma clearance and extended terminal elimination which may prolong postoperative recovery.

Elderly patients (aged 65 years or older) may have increased sensitivity to alfentanil. 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 Alfentanil HCl Injection slowly in geriatric patients [see Warnings and Precautions (5.6)].

This drug 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

Alfentanil HCl Injection should be administered with caution 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

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

8.8 Respiratory Impairment

Alfentanil HCl Injection should be used with caution in patients with pulmonary disease, decreased respiratory reserve, or potentially compromised respiration, in such patients opioids may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration.

9.1 Controlled Substance

Alfentanil HCl Injection contains alfentanil, a Schedule II controlled substance.

9.2 Abuse

Alfentanil HCl Injection contains alfentanil, a substance with a high potential for abuse similar to other opioids including morphine, sufentanil etc. Alfentanil HCl Injection can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

Alfentanil HCl Injection, like other opioids, can be diverted for non-medical 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 re-evaluation 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 chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/ antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Alfentanil HCl Injection should not be abruptly discontinued [see Dosage and Administration (2.13)]. If Alfentanil HCl Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, 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 Alfentanil HCl Injection 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, 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 techniques. If respiratory depression is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive agents may be required to manage hemodynamic instability.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to alfentanil overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to alfentanil overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of alfentanil in Alfentanil HCl 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 begun with care and by titration with smaller than usual doses of the antagonist.

12.1 Mechanism of Action

Alfentanil HCl Injection is an opioid agonist. The principal actions of therapeutic value are analgesia and sedation.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Alfentanil HCl Injection is administered intravenously for the induction of analgesia and anesthesia.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Storage: Store at 20° to 25°C (68 to 77°F). [See USP Controlled Room Temperature]. Protect from light.

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AFA0N Rev. 05/22