Fentanyl (nasal)

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# Black Box Warning

# Overview
Fentanyl (nasal) is a opiod analgesic that is FDA approved for the treatment of breakthrough pain in cancer breakthrough pain in cancer,. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include application site reaction, diaphoresis, pruritus, abdominal pain (transdermal, 3% to 10% ; sublingual, 1% or greater ), constipation (adults, , diarrhea, indigestion (transdermal, loss of appetite, nausea, vomiting, xerostomia, asthenia, confusion , dizziness, feeling nervous, headache, insomnia, somnolence, psychiatric: Anxiety, depression, euphoria, hallucinations, upper respiratory infection , influenza-like symptoms.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Fentanyl nasal spray is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 60 mg of oral morphine/day, 25 mcg of transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for a week or longer. Patients must remain on around-the-clock opioids when taking fentanyl citrate.
- Fentanyl citrate is contraindicated for patients who are not already tolerant to opioids because life-threatening respiratory depression and death could occur in patients not taking chronic opioids. For this reason, fentanyl citrate is contraindicated in the management of acute or postoperative pain, including headache/migraine, or dental pain.
- Fentanyl citrate is intended to be prescribed only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.
- As a part of the TIRF REMS Access program, fentanyl citrate may be dispensed only to outpatients enrolled in the program. For inpatient administration of fentanyl citrate (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient enrollment is not required.
- Healthcare professionals who prescribe fentanyl citrate on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of fentanyl citrate.
- As with all opioids, the safety of patients using such products is dependent on healthcare professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.
- Open the child-resistant container just prior to product use and always replace the bottle in the child-resistant container between doses.
- The goal of dose titration is to find the individual patient's effective and tolerable dose. The dose of fentanyl citrate is not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and MUST be determined by dose titration.
- Starting Dose: Individually titrate fentanyl citrate to a dose that provides adequate analgesia with tolerable side effects. Begin treatment of all patients (including those switching from another fentanyl product) using ONE 100 mcg spray of fentanyl citrate (1 spray in one nostril). Due to differences in pharmacokinetic properties and individual variability, do not switch patients on a mcg per mcg basis from any other fentanyl product to fentanyl citrate as fentanyl citrate is not equivalent with any other fentanyl product, nor is fentanyl citrate a generic version of any other fentanyl product.
- If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg single spray, treat subsequent episodes of breakthrough pain with this dose.
- Titration steps: If adequate analgesia is not achieved with the first 100 mcg dose, dose escalate in a step-wise manner over consecutive episodes of breakthrough pain until adequate analgesia with tolerable side effects is achieved.
- Patients MUST wait at least 2 hours before treating another episode of breakthrough cancer pain with fentanyl citrate.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fentanyl (nasal) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Fentanyl (nasal) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fentanyl (nasal) in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fentanyl (nasal) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Fentanyl (nasal) in pediatric patients.

# Contraindications
There is limited information regarding Fentanyl (nasal) Contraindications in the drug label.

# Warnings
- Serious or fatal respiratory depression can occur even at recommended doses in patients using fentanyl citrate. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.
- Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
- Fentanyl citrate is NOT equivalent to other fentanyl products used to treat breakthrough pain on a mcg per mcg basis. There are differences in the pharmacokinetics of fentanyl citrate relative to other fentanyl products which could potentially result in clinically important differences in the amount of fentanyl absorbed and could result in a fatal overdose.
- When prescribing fentanyl citrate to a patient, DO NOT convert from other fentanyl products. Directions for safely converting patients to fentanyl citrate from other fentanyl products are not currently available. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid-tolerant patients starting treatment for breakthrough pain, the initial dose of fentanyl citrate is 100 mcg. Individually titrate each patient's dose to provide adequate analgesia while minimizing side effects.
- When dispensing fentanyl citrate to a patient, DO NOT substitute it for any other fentanyl product prescription.
- Patients and their caregivers must be instructed that fentanyl citrate contains medicine in an amount that could be fatal to a child.
- Patients and their caregivers must be instructed to keep both used and unused bottles in their child-resistant container and out of the reach of children at all times. Partially used bottles represent a special risk to children. As soon as they are no longer required, all used, unopened or partially used bottles must be completely emptied of accessible fentanyl solution by spraying the remaining contents into the carbon-lined pouch. The sealed pouch and the empty bottle should be put into the child-resistant container before discarding in the trash. Hands must be washed with soap and water immediately after handling the pouch.
- Physicians and dispensing pharmacists must question patients and caregivers specifically about the presence of children in the home on a full-time or visiting basis and counsel accordingly regarding the dangers to children of inadvertent exposure to fentanyl citrate.
- Fentanyl citrate could be fatal to individuals for whom it is not prescribed and for those who are not opioid tolerant.
- The concomitant use of fentanyl citrate with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects.
- Patients on concomitant CNS depressants must be monitored for a change in opioid effects and may require adjustment of the dose of fentanyl citrate.
- Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking fentanyl citrate of these dangers and counsel them accordingly.
- Because potent opioids can cause respiratory depression, cautiously adjust the dose of fentanyl citrate in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of fentanyl citrate may further decrease respiratory drive to the point of respiratory failure.
- Administer fentanyl citrate with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury; only use opioids if clinically warranted.
- Intravenous fentanyl may produce bradycardia. Use fentanyl citrate with caution in patients with bradyarrhythmias.
- Fentanyl citrate is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
- Because of the risk of misuse, abuse, addiction, and overdose, fentanyl citrate is available only through a restricted program under a REMS called the TIRF REMS Access program.
- Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of fentanyl citrate, patient and prescriber enrollment is not required.
- Required components of the TIRF REMS Access program are:
- Healthcare professionals who prescribe fentanyl citrate must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
- To receive fentanyl citrate, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
- Pharmacies that dispense fentanyl citrate must enroll in the program and agree to comply with the REMS requirements.
- Wholesalers and distributers that distribute fentanyl citrate must enroll in the program and distribute only to authorized pharmacies.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of fentanyl citrate has been evaluated in a total of 523 opioid-tolerant patients with breakthrough cancer pain. The average duration of therapy in patients in the long-term study was 73 days, with 153 patients being treated for over 3 months. Patients continuing into the open-label extension period of the safety study have been treated for up to 26 months.
- The most commonly observed adverse events seen with fentanyl citrate are typical of opioid side effects, such as nausea, constipation, somnolence, and headache. Expect opioid side effects and manage them accordingly.
- The clinical trials of fentanyl citrate were designed to evaluate safety and efficacy in treating breakthrough cancer pain; all patients were also taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone, or transdermal fentanyl, for their persistent cancer pain. The adverse reaction data presented in Table 1 reflect the actual percentage of patients experiencing each adverse effect among patients who received fentanyl citrate for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of fentanyl citrate therapy, or cancer-related symptoms. Adverse events are included regardless of causality or severity.
- Table 1 lists adverse reactions with an overall frequency of 5% or greater within the total population that occurred during titration by maximum dose received. The ability to assign fentanyl citrate a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.

## Postmarketing Experience
- Eye disorders: dry eye, swelling, ptosis, strabismus
- Blood and Lymphatic System Disorders: anemia, neutropenia
- Cardiac Disorders: cardiorespiratory arrest
- Gastrointestinal Disorders: vomiting, nausea, constipation, diarrhea, abdominal pain, gastritis, ascites, dry mouth, dyspepsia, mouth ulcer, proctalgia
- General Disorders and Administration Site Conditions: pyrexia, fatigue, edema peripheral, asthenia, edema
- Hepatobiliary Disorders: jaundice
- Immune System Disorders: hypersensitivity
- Infections and Infestations: urinary tract infection, pneumonia, nasopharyngitis, infection, rhinitis, upper respiratory tract infection, bronchitis
- Injury, Poisoning and Procedural Complications: fall
- Investigations: weight decreased, blood alkaline phosphatase increased
- Metabolism and Nutrition Disorders: dehydration, decreased appetite, hyperglycemia, anorexia
- Musculoskeletal and Connective Tissue Disorders: back pain, pain in extremity, arthralgia
- Nervous System Disorders: dizziness, somnolence, headache, dysgeusia
- Psychiatric Disorders: anxiety, insomnia, depression, confusional state, disorientation, agitation
- Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, cough, pharyngolaryngeal pain, nasal discomfort, rhinorrhea, nasal congestion, postnasal drip, pulmonary embolism
- Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, decubitus ulcer, mouth ulceration
- Vascular Disorders: hypertension, deep vein thrombosis

# Drug Interactions
- Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when fentanyl citrate is given concurrently with agents that affect CYP3A4 activity.
- The concomitant use of fentanyl citrate with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl citrate who begin therapy with, or increase the dose of, CYP3A4 inhibitors are to be carefully monitored for signs of opioid toxicity over an extended period of time. Increase dose conservatively.
- The concomitant use of fentanyl citrate with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin], pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of fentanyl citrate. Patients receiving fentanyl citrate who stop therapy with, or decrease the dose of, CYP3A4 inducers may experience sudden increase in fentanyl plasma concentrations and are to be monitored for signs of increased fentanyl citrate activity. Adjust the dose of fentanyl citrate accordingly.
- The presence of allergic rhinitis is not expected to affect fentanyl citrate absorption. However, co-administration of a vasoconstrictive nasal decongestant such as oxymetazoline to treat allergic rhinitis leads to lower peak plasma concentrations and a delayed Tmax of fentanyl that may cause fentanyl citrate to be less effective in patients with allergic rhinitis who use such decongestants, thus potentially impairing pain management. Additionally, in view of the possibility that the titration of a patient while they are experiencing an acute episode of rhinitis could lead to incorrect dose identification (particularly if they are using a vasoconstrictive decongestant), titration under these circumstances must be avoided.
- Concomitant use of fentanyl citrate with an MAO inhibitor, or within 14 days of discontinuing an MAO inhibitor, is not recommended.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women.
- Use fentanyl citrate during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.
- Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.
- In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.
- Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
- Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for fentanyl citrate.
- Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21 of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic. The high dose was approximately 3 times the human dose of 800 mcg per pain episode on a mg/m2 basis. Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation days 6 to 18 was embryo or fetal toxic and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but it was not teratogenic.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fentanyl (nasal) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Fentanyl (nasal) during labor and delivery.

### Nursing Mothers
There is no FDA guidance on the use of Fentanyl (nasal) with respect to nursing mothers.

### Pediatric Use
There is no FDA guidance on the use of Fentanyl (nasal) with respect to pediatric patients.

### Geriatic Use
- Of the 523 opioid tolerant cancer patients with breakthrough cancer pain in clinical studies of fentanyl citrate, 148 (28%) were aged 60 years and over. No clinically meaningful difference was noted in the safety profile of the group aged over 60 years versus that of younger patients in fentanyl citrate clinical trials.
- Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously compared with the younger population. Therefore, exercise caution when individually titrating fentanyl citrate in elderly patients.

### Gender
There is no FDA guidance on the use of Fentanyl (nasal) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Fentanyl (nasal) with respect to specific racial populations.

### Renal Impairment
- Insufficient information exists to make recommendations regarding the use of fentanyl citrate in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via the human CYP3A4 isoenzyme system and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, it is to be used with caution because of the hepatic metabolism and renal excretion of fentanyl.
- It is recommended that fentanyl citrate be titrated to clinical effect for all patients with special care taken in patients with severe renal or hepatic disease.

### Hepatic Impairment
There is no FDA guidance on the use of Fentanyl (nasal) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fentanyl (nasal) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Fentanyl (nasal) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Nasal

### Monitoring
There is limited information regarding Monitoring of Fentanyl (nasal) in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Fentanyl (nasal) in the drug label.

# Overdosage
The manifestations of overdosage with fentanyl citrate are expected to be similar to those for intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant adverse effect being hypoventilation.
- Immediate management of opioid overdose includes removal of the fentanyl citrate pectin gel, if still in the nostril, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, ventilatory status, and circulatory status.
- Provide ventilatory support, obtain intravenous access, and administer naloxone or other opioid antagonists as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use.
- Provide ventilatory support and obtain intravenous access as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.
- Management of severe fentanyl citrate overdose includes: securing a patent airway, assisting or controlling ventilation, and establishing intravenous access. In the presence of hypoventilation or apnea, assist or control ventilation, and administer oxygen as indicated.
- Carefully observe and appropriately manage overdosed patients until their clinical condition is well controlled.
- Although muscle rigidity interfering with respiration has not been observed following the use of fentanyl citrate, this is possible with fentanyl and other opioids. If it occurs, manage by the use of assisted or controlled ventilation, by administration of an opioid antagonist, and, as a final alternative, by the administration of a neuromuscular blocking agent.

# Pharmacology
There is limited information regarding Fentanyl (nasal) Pharmacology in the drug label.

## Mechanism of Action
- Fentanyl is a pure opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, hydromorphone, codeine, and hydrocodone.

## Structure

## Pharmacodynamics
- Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence, respiratory depression and death.
- Analgesia: In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance to any and all opioids.
- The rate of development of tolerance varies widely among individuals. As a result, individually titrate the dose of fentanyl citrate to achieve the desired effect.
- Central Nervous System: The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu-opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.
- Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation.
- Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).
- Gastrointestinal System: Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary, and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
- Cardiovascular System: Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
- Endocrine System: Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species (e.g., rats and dogs). Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.
- Respiratory System: All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects.
- Serious or fatal respiratory depression can occur even at recommended doses. Fentanyl depresses the cough reflex as a result of its CNS activity. Although not observed with fentanyl citrate, in clinical trials, fentanyl given rapidly by intravenous injection in large doses has interfered with respiration by causing rigidity in the muscles of respiration.

## Pharmacokinetics
- In a pharmacokinetic study that evaluated multiple-dose pharmacokinetics of fentanyl citrate when two doses of fentanyl citrate are administered in the same nostril and are separated by a 1, 2 or 4 h time lapse, Cmax2 (Cmax after second administration) was greater than Cmax1 (Cmax after first administration), by 30% when fentanyl citrate was administered 1 h apart, by 25% when fentanyl citrate was administered 2 h apart and by 10% when fentanyl citrate was administered 4 h apart. Based on these results and based on Tmax range of fentanyl citrate observed across pharmacokinetic studies, and frequency of breakthrough pain episodes in a cancer population, a waiting period of 2 h between two consecutive doses of fentanyl citrate is recommended.
- In a pharmacokinetic study to evaluate differences in fentanyl citrate absorption in individuals with induced allergic (seasonal) rhinitis, no clinically meaningful differences were observed in rate or extent of exposure to fentanyl, when compared to the Asymptomatic (Unchallenged) state, indicating that presence of allergic rhinitis does not affect fentanyl citrate absorption. This study also assessed differences in fentanyl citrate absorption, if any, when co-administered with oxymetazoline, a nasal decongestant in subjects undergoing treatment for seasonal allergic rhinitis. Mean Cmax values for Treated arm (Rhinitis treated with oxymetazoline) were about 32% and 40% lower and mean AUCt values were about 10% and 17% lower for Ragweed and Tree pollen induced cohorts respectively as compared to the Asymptomatic arm in each cohort. In addition, mean Tmax of fentanyl citrate in the Treated arm was 0.75 h (range 0.08-3 h) for the Ragweed pollen induced cohort and 1.25 h (range 0.08-3 h) for Tree pollen induced cohort as compared to 0.25 h (0.17-1 h) and 0.33 h (0.17-2 h) for the Asymptomatic arm in each cohort respectively. These results indicate that co-administration with oxymetazoline leads to lower peak plasma concentrations and delayed Tmax of fentanyl citrate.
- Distribution: Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The mean volume of distribution at steady state (Vss) was 4 L/kg.
- Metabolism: The metabolic pathways following intranasal administration of fentanyl citrate have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active.
- Elimination: The disposition of fentanyl following intranasal administration of fentanyl citrate has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important.
- The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Fentanyl (nasal) in the drug label.

# Clinical Studies
There is limited information regarding Clinical Studies of Fentanyl (nasal) in the drug label.

# How Supplied
- Fentanyl citrate is supplied in a 5.3 ml capacity clear glass bottle with an attached metered-dose nasal spray pump incorporating a visual and audible spray counter, and a protective dust cover. Each bottle contains a net fill weight of 1.57 grams and, after priming, delivers 8 sprays. The pump will remain primed for up to 5 days after priming or use. The nasal spray delivers 8 full sprays. There are 2 product strengths and each 100 mcL spray contains either 100 mcg or 400 mcg of fentanyl. Each bottle is supplied in a child-resistant container.
- Bottles in their child-resistant containers are supplied in cartons containing 1 or4 bottles with instructions for use.
- Each carton contains one carbon-lined pouch per bottle for disposal of priming sprays, unwanted doses and residual fentanyl solution.

## Storage
There is limited information regarding Fentanyl (nasal) Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Fentanyl (nasal) in the drug label.

# Precautions with Alcohol
- Alcohol-Fentanyl (nasal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- LAZANDA

# Look-Alike Drug Names
There is limited information regarding Fentanyl (nasal) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price