Drug Safety-related Labeling Changes (SrLC)

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ALFENTA (NDA-019353)

(ALFENTANIL HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/22/2025 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

… Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, 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.

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

…

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

5.11 Risks of Gastrointestinal Complications

Additions and/or revisions underlined:

…

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.11)].

7 Drug Interactions

Additions and/or revisions underlined:

…

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.11)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Clinical Considerations

…

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.

…

12/15/2023 (SUPPL-29)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF ALFENTANIL HCL INJECTION

Addiction, Abuse, and Misuse

Because the use of Alfentanil HCl Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Alfentanil HCl Injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Alfentanil HCl Injection are essential [see Warnings and Precautions (5.2)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Alfentanil HCl Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3), Drug Interactions (7)].

Cytochrome P450 3A4 Interaction

The concomitant use of Alfentanil HCl Injection with all cytochrome P450 3A4 inhibitors may result in an increase in alfentanil plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in alfentanil plasma concentration. Monitor patients receiving Alfentanil HCl Injection and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.4), Drug Interactions (7), Clinical Pharmacology (12.3)].

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

…

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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.

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

Additions and/or revisions underlined:

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 sedation and respiratory depression, particularly when initiating therapy with Fentanyl Citrate Injection increasing intracranial pressure.

Opioids may also obscure the clinical course in a patient with a head injury.

5.13 Risks of Driving and Operating Machinery

New subsection added:

Fentanyl Citrate Injection may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery after Fentanyl Citrate Injection administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Fentanyl Citrate Injection and know how they will react to the medication.

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

When benzodiazepines or other CNS depressants are used with Alfentanil HCl 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 HCl Injection are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

…

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Alfentanil HCl 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 HCl 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

Additions and/or revisions underlined:

…

Concomitant use of Alfentanil HCl Injection with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could result in lower than expected alfentanil plasma concentrations, decrease efficacy, or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to alfentanil. 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)].

5.6 Opioid-Induced Hyperalgesia and Allodynia

New subsection added:

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

Additions and/or revisions underlined:

…

 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 HCl Injection if serotonin syndrome is suspected.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6)]

  6.2 Postmarketing Experience

  Additions and/or revisions underlined:

  …

  Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology (12.2)].

  Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6)]

  Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

  …

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Alfentanil HCl Injection in pregnant women are insufficient to inform a drug- associated risk for major birth defects and miscarriage.

…

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth

…

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added section:

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.

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 Adverse Reactions (6), Clinical Pharmacology (12.2)].

10/07/2019 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Life-Threatening Respiratory Depression

Newly added information to the end of the subsection:

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.

5.6 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Additions and/or revisions underline

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). This may occur within the recommended dosage range.

Additions and/or revisions to subsection title underlined below:

5.11 Increased Risk of Seizures in Patients with Compulsive or Seizure Disorders

7 Drug Interactions

Table 2: Clinically Significant Drug Interactions with Alfentanil HCl Injection

Serotonergic Drugs

Additions and/or revisions underlined in the following table section:

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

12/16/2016 (SUPPL-21)

Approved Drug Label (PDF)

Boxed Warning

(Newly added due to PLR format conversion)

WARNING: ADDICTION, ABUSE, AND MISUSE

Addiction, Abuse, and Misuse

Alfentanil HCl injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Alfentanil HCl Injection, and monitor all patients regularly for the development of these behaviors and conditions.

4 Contraindications

Additions and/or revisions underlined:

Alfentanil HCl Injection is contraindicated in patients with:

• Hypersensitivity to alfentanil (e.g., anaphylaxis)

5 Warnings and Precautions

Physician Labeling Rule (PLR) conversion; additions and/or revisions underlined:

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.

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.

5.10 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 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.

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. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. 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.  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.

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, 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.

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.

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 …

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.

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), 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). 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 …

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.

6 Adverse Reactions

(Addition of the following line listing)

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse

• Life-Threatening Respiratory Depression

• Muscle Rigidity and Skeletal Muscle Movement

• Interactions with Benzodiazepines and CNS Depressants

• Serotonin Syndrome

• Bradycardia

• Gastrointestinal Adverse Reactions

• Seizures

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 …

6.2 Postmarketing Experience

(Newly added section)

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.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Alfentanil HCl Injection.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

The adverse experience profile from 696 …  during MAC included hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving alfentanil for MAC, in order of decreasing frequency, were nausea, hypotension, vomiting, pruritus, confusion, somnolence and agitation.

7 Drug Interactions

PLR conversion:

Table 2 includes clinically significant drug interactions with Alfentanil HCl Injection.

Table 2: Clinically Significant Drug Interactions with Alfentanil HCl Injection

Information has been converted to a table format; please refer to label.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion:

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Alfentanil HCl Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, alfentanil reduced pup birth weights and increased pup mortality when administered to pregnant rats during gestation and throughout lactation at 9 times the human dose of 335 mcg/kg per procedure. Alfentanil was embryocidal when administered to pregnant rabbits during organogenesis at 72.6 times the human dose of 335 mcg/kg per procedure. No malformations were noted in rats or rabbits treated with alfentanil during organogenesis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Alfentanil HCl Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Alfentanil HCl Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

Pregnant rats were treated with intravenous alfentanil doses of 0.08, 0.31, or 1.25 mg/kg/day (2.3, 9, or 36.6 times the human total dose of 335 mcg/kg based on body surface area, respectively). No malformations or embryotoxic effects were noted despite maternal toxicity (increased mortality in the mid- and high-dose group).

Pregnant rabbits were treated with intravenous alfentanil doses of 0.08, 0.31, or 1.25 mg/kg/day (4.6, 18, or 72.6 times the human total dose of 335 mcg/kg based on body surface area, respectively). Decreased live fetuses per litter and decreased litter size in the high dose group were noted in the presence of maternal toxicity (decreased body weight gain and mortality in the high-dose group).

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered 8 mg/kg/day alfentanil (232 times the human dose of 335 mcg/kg/day based on body surface area) continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously implanted osmotic minipumps.

Pregnant rats were treated intravenously with alfentanil 0.08, 0.31, or 1.25 mg/kg/day (2.3, 9, or 36.6 times the human total dose of 335 mcg/day based on body surface area, respectively) during gestation and throughout lactation. Reduced birth weights and decreased pup survival were noted in the mid- and high-dose groups in the presence of maternal toxicity (increased mortality in the mid- and high-dose groups).

8.2 Lactation

PLLR conversion:

Risk Summary

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Alfentanil HCl Injection and any potential adverse effects on the breastfed infant from Alfentanil HCl Injection or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Alfentanil HCl Injection through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

PLLR conversion:

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

8.5 Geriatric Use

PLR conversion; additional information below:

… 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.

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

(Newly added section)

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

(Newly added section)

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

(Newly added section)

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.

Other

PLR conversion; additional revisions to incorporate the opioid analgesic template language.