Generic Name: fentanyl (FEN-ta-nil)
Brand Name: Sublimaze

Fentanyl is used for:

Producing anesthesia for surgery and treating pain before, during, and after surgery. It may also be used with other medicines.

Fentanyl is a narcotic (opioid) analgesic. It works in the brain and nervous system to cause anesthesia and decrease pain.

Do NOT use fentanyl if:

• you are allergic to any ingredient in fentanyl or any related medicine (eg, sufentanil)
• you take sibutramine or sodium oxybate (GHB)

Contact your doctor or health care provider right away if any of these apply to you.

Before using fentanyl:

Some medical conditions may interact with fentanyl. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding
• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
• if you have allergies to medicines, foods, or other substances
• if you have diabetes; asthma, chronic obstructive pulmonary disease (COPD), or other breathing problems; fever; increased pressure or unusual growths in the brain; heart problems; liver or kidney disease; pancreatitis; poor health or nutrition; or a recent head injury
• if you have a history of slow or irregular heartbeat or blood pressure problems
• if you take a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) or have taken one within the past 14 days

Some MEDICINES MAY INTERACT with fentanyl. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Mixed agonist/antagonist analgesics (eg, buprenorphine, pentazocine, butorphanol), naltrexone, or rifamycins (eg, rifampin) because the effectiveness of fentanyl may be decreased
• Amiodarone, aprepitant, azole antifungals (eg, fluconazole), benzodiazepines (eg, alprazolam), cimetidine, diltiazem, HIV protease inhibitors (eg, ritonavir), macrolide antibiotics (eg, erythromycin), MAOIs (eg, phenelzine), nefazodone, phenothiazines (eg, chlorpromazine), serotonin reuptake inhibitors (eg, citalopram), sibutramine, sodium oxybate (GHB), telithromycin, or verapamil because the risk of side effects may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if fentanyl may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use fentanyl:

Use fentanyl as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Fentanyl is usually administered as an injection at your doctor's office, hospital, or clinic.
• If fentanyl contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.
• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.
• If you miss a dose of fentanyl, contact your doctor immediately.

Ask your health care provider any questions you may have about how to use fentanyl.

Important safety information:

• Fentanyl may cause drowsiness or dizziness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to fentanyl. Using fentanyl alone, with certain other medicines, or with alcohol may lessen your ability to drive or to perform other potentially dangerous tasks.
• Avoid drinking alcohol while taking fentanyl.
• Check with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using fentanyl; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.
• Tell your doctor or dentist that you take fentanyl before you receive any medical or dental care, emergency care, or surgery.
• Use fentanyl with caution in the ELDERLY because they may be more sensitive to its effects.
• Use fentanyl with extreme caution in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed.
• PREGNANCY and BREAST-FEEDING: If you are pregnant or plan on becoming pregnant, contact your doctor. You will need to discuss the benefits and risks of using fentanyl while you are pregnant. Fentanyl is found in breast milk. If you are or will be breast-feeding while you are using fentanyl, check with your doctor. Discuss any possible risks to your baby.

Some people who use fentanyl for a long time may develop a need to continue taking it. People who take high doses are also at risk. This is known as DEPENDENCE or addiction.

Possible side effects of fentanyl:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Anxiety; confusion; constipation; difficulty walking; dizziness; drowsiness; dry mouth; headache; indigestion; itching; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision; fainting; hallucinations; muscle rigidity; seizures; severe or persistent dizziness, headache, or light-headedness; slow or irregular heartbeat; slow or shallow breathing; trouble breathing; weakness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center ( http://www.aapcc.org), or emergency room immediately.

Proper storage of fentanyl:

Fentanyl is usually handled and stored by a health care provider. If you are using fentanyl at home, store fentanyl as directed by your pharmacist or health care provider. Keep fentanyl out of the reach of children and away from pets.

General information:

• If you have any questions about fentanyl, please talk with your doctor, pharmacist, or other health care provider.
• Fentanyl is to be used only by the patient for whom it is prescribed. Do not share it with other people.
• If your symptoms do not improve or if they become worse, check with your doctor.
• Check with your pharmacist about how to dispose of unused medicine.

This information should not be used to decide whether or not to take fentanyl or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about fentanyl. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to fentanyl. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using fentanyl.

Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using this medicine.

Usual Adult Dose for Chronic Pain

TRANSDERMAL PATCH:
-Due to the risk of respiratory depression, the transdermal patch is for use in opioid-tolerant patients only; opioid tolerant patients have been taking at least: morphine 60 mg daily, oral oxycodone 30 mg daily, oral hydromorphone 8 mg daily, or an equianalgesic dose of another opioid for 1 week or longer.
-Discontinue all other extended-release opioids when beginning therapy.

Initial doses: The initial dose should be individualized taking into account the patient's prior treatment experience. This dose may be calculated based on the dose conversion guidelines in the product package insert, local protocol, or another reliable reference; when calculating, be aware there is substantial inter-patient variability in the relative potency of different opioid drugs and products and therefore it is preferable to underestimate a 24-hour fentanyl requirement and provide rescue medication than to overestimate which could result in adverse reactions.
Dose titration:
-Initial: May increase dose after 3 days based on the daily dose of supplemental opioid analgesics required by the patient on the second or third day of the initial application.
-Further titration should occur after no less than two 3-day applications as it may take up to 6 days for fentanyl levels to reach equilibrium. Titration should be based on the daily dose of supplementary opioids required and the following ratio may be used: Increase transdermal fentanyl by 12 mcg//hr for use of supplemental oral morphine doses of 45 mg/24 hours.
Maintenance dose: Adjust dose to obtain an appropriate balance between pain management and opioid-related adverse reactions. During chronic therapy, periodically reassess the continued need for opioid analgesics.

Comments:
-Do not begin a patient on a fentanyl transdermal patch as their first opioid..
-A small number of patients may require a 48-hour dosing interval; an increase in dose should be evaluated before changing dosing intervals.
-For delivery rates in excess of 100 mcg/hour, multiple systems may be used.

Use: For the management of pain in opioid-tolerant patients, severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Usual Adult Dose for Breakthrough Pain

TRANSMUCOSAL PRODUCTS
-For use in patients who are opioid-tolerant and taking around-the-clock opioids. Opioid tolerant patients have been taking at least: morphine 60 mg daily, oral oxycodone 30 mg daily, oral hydromorphone 8 mg daily, or an equianalgesic dose of another opioid for 1 week or longer.
-All transmucosal products must be individually titrated to an effective and tolerable dose. Once titrated, these products are used to treat up to 4 episodes of breakthrough pain a day; if a patient is experiencing more than 4 breakthrough episodes per day, the around-the-clock opioid dose should be re-evaluated. If the around-the-clock opioid dose is adjusted, re-adjustment of the transmucosal product may be necessary.
-Transmucosal fentanyl products are not bioequivalent; patients should not be interchanged on a mcg per mcg basis from 1 fentanyl product to any other fentanyl product

TRANSMUCOSAL LOZENGE (Actiq(R))
Initial dose: 200 mcg consumed over 15 minutes
Dose titration: If breakthrough pain is not relieved 15 minutes after completion of 1 unit (30 minutes after start), 1 additional unit of the same strength may be taken; Patients must wait at least 4 hours before re-treating. If breakthrough pain had not been relieved with 1 unit, the dose should be increased to the next highest strength with subsequent episodes of pain.
Maintenance dose: An effective dose is achieved when 1 unit is mostly sufficient to treat an episode of breakthrough pain; however, if there is inadequate analgesia a second dose of the same strength may be given 15 minutes after completion (30 minutes after start); no more than 2 doses should be used to treat any episode of breakthrough pain.
Maximum dose: 4 breakthrough episodes per day at intervals of at least 4 hours

Comments: The lozenge should be placed in mouth between cheek and lower gum and sucked; occasionally move from side to side using the handle; do not chew.
-If signs of excessive opioid effects appear before the unit is consumed, the unit should be removed immediately and subsequent doses should be decreased.

NASAL SPRAY (Lazanda(R))
Initial dose: 100 mcg sprayed in 1 nostril
Dose titration: If adequate analgesia is not achieved after 30 minutes, the dose should be escalated in a step-wise manner (100 to 200 to 400 to 800 mcg) over consecutive episodes. Patients must wait at least 2 hours between doses. Patients should confirm the dose that works for them with a second episode of breakthrough pain.
Maintenance dose: Once an effective dose has been established, patients should use that dose for each subsequent breakthrough episode.
Maximum dose: 800 mcg per dose; 4 breakthrough episodes per day at intervals of at least 2 hours

SUBLINGUAL TABLETS (Abstral(R))
Initial dose: 100 mcg sublingually
Dose titration: If adequate analgesia is not obtained after 30 minutes, a second dose of the same strength may be taken. Patients must wait at least 2 hours before re-treating. Dose escalation should proceed in a stepwise manner (200 to 300 to 400 to 600 to 800 mcg) as needed. During titration, multiples of 100 mcg and/or 200 mcg tablets may be used for any single dose. Patients should not use more than 4 tablets at one time.
Maintenance dose: An effective dose is achieved when 1 dose is sufficient to treat most episodes of breakthrough pain; however, if there is inadequate analgesia a second dose of the same strength may be given after 30 minutes; no more than 2 doses should be used to treat any episode of breakthrough pain. Patients should limit treatment to 4 or fewer breakthrough episodes per day.
Maximum dose: 4 episodes per day; 800 mcg per dose at intervals of at least 2 hours

Comments: The sublingual tablet should be placed on the floor of the mouth and allowed to completely dissolve; do not eat or drink until the tablet is completely dissolved.
-The initial dose of the sublingual tablet is always 100 mcg except in patients receiving the transmucosal lozenge - see dose adjustment section for initial dosing recommendations for these patients.

SUBLINGUAL SPRAY:
Initial dose: 100 mcg sprayed sublingually
Dose titration: If adequate analgesia is not obtained after 30 minutes, a second dose of the same strength may be used. Patients must wait at least 4 hours before re-treating. If breakthrough pain is not relieved with the 100 mcg dose, dose escalation should proceed in a stepwise manner (200 to 400 to 600 to 800 to 1200 to 1600 mcg) for subsequent episodes of pain.
Maintenance dose: An effective dose is achieved when 1 dose is sufficient to treat most episodes of breakthrough pain; however, if there is inadequate analgesia a second dose of the same strength may be given after 30 minutes; no more than 2 doses should be used to treat any episode of breakthrough pain. Patients should limit treatment to 4 or fewer breakthrough episodes per day.
Maximum dose: 4 episodes per day at intervals of at least 4 hours

Comments: Spray into mouth underneath the tongue.
-The initial dose of is always 100 mcg except in patients receiving the transmucosal lozenge - see dose adjustment section for initial dosing recommendations for these patients.

BUCCAL TABLETS (Fentora(R))
Initial dose: 100 mcg buccally
Dose titration: If adequate analgesia is not obtained after 30 minutes, a second dose of the same strength may be taken. Patients must wait at least 4 hours before re-treating. If breakthrough pain is not relieved with 100 mcg, the next dose should be two 100 mcg tablets (one on each side of the mouth in the buccal cavity). The patient may be further titrated in a stepwise manner. During titration, multiples of 100 mcg or 200 mcg tablets may be used for any single dose. Patients should not use more than 4 tablets at one time.
Maintenance dose: An effective dose is achieved when 1 dose is sufficient to treat most episodes of breakthrough pain; however, if there is inadequate analgesia a second dose of the same strength may be given after 30 minutes; no more than 2 doses should be used to treat any episode of breakthrough pain. Patients should limit treatment to 4 or fewer breakthrough episodes per day.
Maximum dose: 4 episodes per day; at intervals of at least 4 hours

Comments: Tablet should be placed in the buccal cavity (above the rear molar, between the upper cheek and gum); alternatively, may be placed under the tongue.
-The initial dose of is always 100 mcg except in patients receiving the transmucosal lozenge - see dose adjustment section for initial dosing recommendations for these patients.

Use: For the management of breakthrough pain in patients who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

Usual Adult Dose for Pain

IONTOPHORETIC TRANSDERMAL SYSTEM -For Hospital Use Only
-This system is to be used only after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics.

Initial dose: Apply 1 system transdermally to healthy, unbroken/intact, non-irritated and non-irradiated skin on the chest or upper outer arm
-The patient should be instructed to self-administer doses; to initiate administration, the patient must press and release the button twice within 3 seconds.
-A maximum of six 40 mcg doses can be administered per hour; each on-demand dose is delivered over 10 minutes
-Each unit will operate for up to 24 hours or 80 doses, whichever comes first.
Maximum duration of therapy: 3 days (72 hours)

Comments:
-This system should only be used in patients who are alert enough and have adequate cognitive ability to understand the directions for use; discontinue treatment before patients leave the hospital.
-The system is a for single-use only. After 24 hours or 80 doses have been delivered, the unit will cease functioning; the light and audible beep will no longer function, although the digital display will show the number of doses delivered for an additional 12 hours.
-Only 1 unit should be applied at a time; if analgesia is inadequate, either provide additional analgesic medication or change therapy.
-Gloves should always be warn when handling the system; avoid contact with synthetic materials (such as carpeted floors) during device assembly to reduce the possibility of electrostatic discharge and avoid exposure to electronic security systems as this may damage the system.
-Remove system prior to MRI, cardioversion, defibrillation, or diathermy as the system can be damaged by strong electromagnetic fields; this system contains radio-opaque components that may interfere with an X-ray image or a CT scan.
-TROUBLESHOOTING; In the event the system does not appear to function normally, remove and replace with a new system; consult Product Information for Important Device Instructions including specific electromagnetic compatibility and recommendations to minimize electromagnetic interference.

Use: For the short-term management of acute postoperative pain in adult patients requiring opioid analgesia in the hospital.

Usual Adult Dose for Anesthesia

Premedication for Anesthesia:
50 to 100 mcg IM, 30 to 60 minutes prior to surgery.
Lozenge: 5 mcg/kg (400 mcg is the maximum dose).
Lower doses should be used for vulnerable patients.

General Anesthesia:
Total Low dose: 2 mcg/kg (minor procedures).
Maintenance low dose: Infrequently needed.
Total Moderate dose: 2 to 20 mcg/kg.
Maintenance moderate dose: 25 to 100 mcg IV/IM.
Total high dose: 20 to 50 mcg/kg (prolonged surgeries).
Maintenance high dose: 25 mcg to half of the initial dose.

Adjunct to Regional Anesthesia:
50 to 100 mcg IM or slow IV over 3 to 5 minutes as required.

Postoperative :
50 to 100 mcg IM. May repeat dose in 1 to 2 hours as needed.

Usual Pediatric Dose for Anesthesia

Doses should be titrated to appropriate effects; wide range of doses exist, dependent upon desired degree of analgesia/anesthesia, clinical environment, patient's status, and presence of opioid tolerance.

Neonates: Analgesia: International Evidence-Based Group for Neonatal Pain recommendations:
Intermittent doses: Slow IV push: 0.5 to 3 mcg/kg/dose
---Continuous IV infusion: 0.5 to 2 mcg/kg/hour
---Sedation/analgesia: Slow IV push: 1 to 4 mcg/kg/dose; may repeat every 2 to 4 hours
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg, then 0.5 to 1 mcg/kg/hour; titrate upward
---Mean required dose: Neonates with gestational age less than 34 weeks: 0.64 mcg/kg/hour; neonates with gestational age greater than or equal to 34 weeks: 0.75 mcg/kg/hour
---Continuous sedation/analgesia during extracorporeal membrane oxygenation (ECMO): Initial IV bolus: 5 to 10 mcg/kg slow IV push over 10 minutes, then 1 to 5 mcg/kg/hour; titrate upward; tolerance may develop; higher doses (up to 20 mcg/kg/hour) may be needed by day 6 of ECMO.

Younger infants:
---Sedation/analgesia: Slow IV push: 1 to 4 mcg/kg/dose; may repeat every 2 to 4 hours
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg, then 0.5 to 1 mcg/kg/hour; titrate upward
---Continuous sedation/analgesia during extracorporeal membrane oxygenation ECMO: Initial IV bolus: 5 to 10 mcg/kg slow IV push over 10 minutes, then 1 to 5 mcg/kg/hour; titrate upward; tolerance may develop; higher doses (up to 20 mcg/kg/hour) may be needed by day 6 of ECMO.

Older Infants and Children 1 to 12 years:
---Sedation for minor procedures/analgesia: IM or IV: 1 to 2 mcg/kg/dose; may repeat at 30 to 60 minute intervals. Note: Children 18 to 36 months of age may require 2 to 3 mcg/kg/dose.
--- Intranasal: Children greater than or equal to 10 kg: 1.5 mcg/kg once (maximum: 100 mcg/dose); reported range: 1 to 2 mcg/kg; some studies allowed for additional incremental doses of 0.5 mcg/kg to be administered every 5 minutes, not to exceed a total dose of 3 mcg/kg depending on pain type and severity.
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg then 1 mcg/kg/hour; titrate upward; usual: 1 to 3 mcg/kg/hour; some require 5 mcg/kg/hour
---Moderate to severe chronic pain: Transdermal patch: Opioid-tolerant children greater than or equal to 2 years receiving at least 60 mg oral morphine equivalents per day: Initial: 25 mcg/hour system or higher, based on conversion to fentanyl equivalents and administration of equianalgesic dosage (see package insert for further information); use short-acting analgesics for first 24 hours with supplemental PRN doses thereafter (for breakthrough pain); dose may be increased after 3 days, based on the daily dose of supplementary PRN opioids required; use the ratio of 45 mg of oral morphine equivalents per day to a 12.5 mcg/hour increase in transdermal patch dosage; change patch every 72 hours; Note: Dosing intervals less than every 72 hours are not recommended for children and adolescents. Initiation of the transdermal patch in children taking less than 60 mg of oral morphine equivalents per day has not been studied in controlled clinical trials; in open-label trials, children 2 to 18 years of age who were receiving at least 45 mg of oral morphine equivalents per day were started with an initial transdermal dose of 25 mcg/hour (or higher, depending upon equianalgesic dose of opioid received).

Children greater than or equal to 5 years and less than 50 kg:
Patient-controlled analgesia (PCA): IV: Opioid-naive: Note: PCA has been used in children as young as 5 years of age; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly. All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed.

Usual concentration: Determined by weight; some clinicians use the following:
---Children less than 12 kg: 10 mcg/mL
---Children 12 to 30 kg: 25 mcg/mL
---Children greater than 30 kg: 50 mcg/mL
---Demand dose: Usual initial: 0.5 to 1 mcg/kg/dose; usual range: 0.5 to 1 mcg/kg/dose
---Lockout: Usual initial: 5 doses/hour
---Lockout interval: Range: 6 to 8 minutes
---Usual basal rate: 0 to 0.5 mcg/kg/hour

Children greater than 12 years to adult:
Sedation for minor procedures/analgesia: IV: 0.5 to 1 mcg/kg/dose; may repeat after 30 to 60 minutes; or 25 to 50 mcg, repeat full dose in 5 minutes if needed, may repeat 4 to 5 times with 25 mcg at 5 minute intervals if needed. Note: Higher doses are used for major procedures.

Continuous sedation/analgesia:
---Less than 50 kg: Initial IV bolus: 1 to 2 mcg/kg; continuous infusion rate: 1 to 2 mcg/kg/hour
---Greater than 50 kg: Initial IV bolus: 1 to 2 mcg/kg or 25 to 100 mcg/dose; continuous infusion rate: 1 to 2 mcg/kg/hour or 25 to 200 mcg/hour

Patient-controlled analgesia (PCA): IV: Children greater than 50 kg, Adolescents greater than 50 kg, and Adults: Note: All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed:

---Usual concentration: 50 mcg/mL
---Demand dose: Usual initial: 20 mcg; usual range: 10 to 50 mcg
---Lockout interval: Usual initial: 6 minutes; usual range: 5 to 8 minutes
---Usual basal rate: less than or equal to 50 mcg/hour

Preoperative sedation, adjunct to regional anesthesia, postoperative pain: IM, IV: 25 to 100 mcg/dose

Adjunct to general anesthesia: Slow IV:
---Low dose: 0.5 to 2 mcg/kg/dose depending on the indication
---Moderate dose: Initial: 2 to 20 mcg/kg/dose; Maintenance (bolus or infusion): 1 to 2 mcg/kg/hour. Discontinuing fentanyl infusion 30 to 60 minutes prior to the end of surgery will usually allow adequate ventilation upon emergence from anesthesia. For "fast-tracking" and early extubation following major surgery, total fentanyl doses are limited to 10 to 15 mcg/kg.
---High dose: 20 to 50 mcg/kg/dose; Note: High dose fentanyl as an adjunct to general anesthesia is rarely used, but is still described in the manufacturer label.

General anesthesia without additional anesthetic agents: IV: 50 to 100 mcg/kg with oxygen and skeletal muscle relaxant

Moderate to severe chronic pain: Transdermal patch: Opioid tolerant patients receiving at least 60 mg oral morphine equivalents per day: Initial: 25 mcg/hour system or higher, based on conversion to fentanyl equivalents and administration of equianalgesic dosage (see package insert for further information); use short-acting analgesics for first 24 hours with supplemental PRN doses thereafter (for breakthrough pain); dose may be increased after 3 days based on the daily dose of supplementary PRN opioids required; use the ratio of 45 mg of oral morphine equivalents per day to a 12.5 mcg/hour increase in transdermal patch dosage; transdermal patch is usually administered every 72 hours but select adult patients may require every 48-hour administration; dosage increase administered every 72 hours should be tried before 48-hour schedule is used.

Usual Pediatric Dose for Pain

Doses should be titrated to appropriate effects; wide range of doses exist, dependent upon desired degree of analgesia/anesthesia, clinical environment, patient's status, and presence of opioid tolerance.

Neonates: Analgesia: International Evidence-Based Group for Neonatal Pain recommendations:
Intermittent doses: Slow IV push: 0.5 to 3 mcg/kg/dose
---Continuous IV infusion: 0.5 to 2 mcg/kg/hour
---Sedation/analgesia: Slow IV push: 1 to 4 mcg/kg/dose; may repeat every 2 to 4 hours
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg, then 0.5 to 1 mcg/kg/hour; titrate upward
---Mean required dose: Neonates with gestational age less than 34 weeks: 0.64 mcg/kg/hour; neonates with gestational age greater than or equal to 34 weeks: 0.75 mcg/kg/hour
---Continuous sedation/analgesia during extracorporeal membrane oxygenation (ECMO): Initial IV bolus: 5 to 10 mcg/kg slow IV push over 10 minutes, then 1 to 5 mcg/kg/hour; titrate upward; tolerance may develop; higher doses (up to 20 mcg/kg/hour) may be needed by day 6 of ECMO.

Younger infants:
---Sedation/analgesia: Slow IV push: 1 to 4 mcg/kg/dose; may repeat every 2 to 4 hours
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg, then 0.5 to 1 mcg/kg/hour; titrate upward
---Continuous sedation/analgesia during extracorporeal membrane oxygenation ECMO: Initial IV bolus: 5 to 10 mcg/kg slow IV push over 10 minutes, then 1 to 5 mcg/kg/hour; titrate upward; tolerance may develop; higher doses (up to 20 mcg/kg/hour) may be needed by day 6 of ECMO.

Older Infants and Children 1 to 12 years:
---Sedation for minor procedures/analgesia: IM or IV: 1 to 2 mcg/kg/dose; may repeat at 30 to 60 minute intervals. Note: Children 18 to 36 months of age may require 2 to 3 mcg/kg/dose.
--- Intranasal: Children greater than or equal to 10 kg: 1.5 mcg/kg once (maximum: 100 mcg/dose); reported range: 1 to 2 mcg/kg; some studies allowed for additional incremental doses of 0.5 mcg/kg to be administered every 5 minutes, not to exceed a total dose of 3 mcg/kg depending on pain type and severity.
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg then 1 mcg/kg/hour; titrate upward; usual: 1 to 3 mcg/kg/hour; some require 5 mcg/kg/hour
---Moderate to severe chronic pain: Transdermal patch: Opioid-tolerant children greater than or equal to 2 years receiving at least 60 mg oral morphine equivalents per day: Initial: 25 mcg/hour system or higher, based on conversion to fentanyl equivalents and administration of equianalgesic dosage (see package insert for further information); use short-acting analgesics for first 24 hours with supplemental PRN doses thereafter (for breakthrough pain); dose may be increased after 3 days, based on the daily dose of supplementary PRN opioids required; use the ratio of 45 mg of oral morphine equivalents per day to a 12.5 mcg/hour increase in transdermal patch dosage; change patch every 72 hours; Note: Dosing intervals less than every 72 hours are not recommended for children and adolescents. Initiation of the transdermal patch in children taking less than 60 mg of oral morphine equivalents per day has not been studied in controlled clinical trials; in open-label trials, children 2 to 18 years of age who were receiving at least 45 mg of oral morphine equivalents per day were started with an initial transdermal dose of 25 mcg/hour (or higher, depending upon equianalgesic dose of opioid received).

Children greater than or equal to 5 years and less than 50 kg:
Patient-controlled analgesia (PCA): IV: Opioid-naive: Note: PCA has been used in children as young as 5 years of age; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly. All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed.

Usual concentration: Determined by weight; some clinicians use the following:
---Children less than 12 kg: 10 mcg/mL
---Children 12 to 30 kg: 25 mcg/mL
---Children greater than 30 kg: 50 mcg/mL
---Demand dose: Usual initial: 0.5 to 1 mcg/kg/dose; usual range: 0.5 to 1 mcg/kg/dose
---Lockout: Usual initial: 5 doses/hour
---Lockout interval: Range: 6 to 8 minutes
---Usual basal rate: 0 to 0.5 mcg/kg/hour

Children greater than 12 years to adult:
Sedation for minor procedures/analgesia: IV: 0.5 to 1 mcg/kg/dose; may repeat after 30 to 60 minutes; or 25 to 50 mcg, repeat full dose in 5 minutes if needed, may repeat 4 to 5 times with 25 mcg at 5 minute intervals if needed. Note: Higher doses are used for major procedures.

Continuous sedation/analgesia:
---Less than 50 kg: Initial IV bolus: 1 to 2 mcg/kg; continuous infusion rate: 1 to 2 mcg/kg/hour
---Greater than 50 kg: Initial IV bolus: 1 to 2 mcg/kg or 25 to 100 mcg/dose; continuous infusion rate: 1 to 2 mcg/kg/hour or 25 to 200 mcg/hour

Patient-controlled analgesia (PCA): IV: Children greater than 50 kg, Adolescents greater than 50 kg, and Adults: Note: All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed:

---Usual concentration: 50 mcg/mL
---Demand dose: Usual initial: 20 mcg; usual range: 10 to 50 mcg
---Lockout interval: Usual initial: 6 minutes; usual range: 5 to 8 minutes
---Usual basal rate: less than or equal to 50 mcg/hour

Preoperative sedation, adjunct to regional anesthesia, postoperative pain: IM, IV: 25 to 100 mcg/dose

Adjunct to general anesthesia: Slow IV:
---Low dose: 0.5 to 2 mcg/kg/dose depending on the indication
---Moderate dose: Initial: 2 to 20 mcg/kg/dose; Maintenance (bolus or infusion): 1 to 2 mcg/kg/hour. Discontinuing fentanyl infusion 30 to 60 minutes prior to the end of surgery will usually allow adequate ventilation upon emergence from anesthesia. For "fast-tracking" and early extubation following major surgery, total fentanyl doses are limited to 10 to 15 mcg/kg.
---High dose: 20 to 50 mcg/kg/dose; Note: High dose fentanyl as an adjunct to general anesthesia is rarely used, but is still described in the manufacturer label.

General anesthesia without additional anesthetic agents: IV: 50 to 100 mcg/kg with oxygen and skeletal muscle relaxant

Moderate to severe chronic pain: Transdermal patch: Opioid tolerant patients receiving at least 60 mg oral morphine equivalents per day: Initial: 25 mcg/hour system or higher, based on conversion to fentanyl equivalents and administration of equianalgesic dosage (see package insert for further information); use short-acting analgesics for first 24 hours with supplemental PRN doses thereafter (for breakthrough pain); dose may be increased after 3 days based on the daily dose of supplementary PRN opioids required; use the ratio of 45 mg of oral morphine equivalents per day to a 12.5 mcg/hour increase in transdermal patch dosage; transdermal patch is usually administered every 72 hours but select adult patients may require every 48-hour administration; dosage increase administered every 72 hours should be tried before 48-hour schedule is used.

Usual Pediatric Dose for Sedation

Doses should be titrated to appropriate effects; wide range of doses exist, dependent upon desired degree of analgesia/anesthesia, clinical environment, patient's status, and presence of opioid tolerance.

Neonates: Analgesia: International Evidence-Based Group for Neonatal Pain recommendations:
Intermittent doses: Slow IV push: 0.5 to 3 mcg/kg/dose
---Continuous IV infusion: 0.5 to 2 mcg/kg/hour
---Sedation/analgesia: Slow IV push: 1 to 4 mcg/kg/dose; may repeat every 2 to 4 hours
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg, then 0.5 to 1 mcg/kg/hour; titrate upward
---Mean required dose: Neonates with gestational age less than 34 weeks: 0.64 mcg/kg/hour; neonates with gestational age greater than or equal to 34 weeks: 0.75 mcg/kg/hour
---Continuous sedation/analgesia during extracorporeal membrane oxygenation (ECMO): Initial IV bolus: 5 to 10 mcg/kg slow IV push over 10 minutes, then 1 to 5 mcg/kg/hour; titrate upward; tolerance may develop; higher doses (up to 20 mcg/kg/hour) may be needed by day 6 of ECMO.

Younger infants:
---Sedation/analgesia: Slow IV push: 1 to 4 mcg/kg/dose; may repeat every 2 to 4 hours
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg, then 0.5 to 1 mcg/kg/hour; titrate upward
---Continuous sedation/analgesia during extracorporeal membrane oxygenation ECMO: Initial IV bolus: 5 to 10 mcg/kg slow IV push over 10 minutes, then 1 to 5 mcg/kg/hour; titrate upward; tolerance may develop; higher doses (up to 20 mcg/kg/hour) may be needed by day 6 of ECMO.

Older Infants and Children 1 to 12 years:
---Sedation for minor procedures/analgesia: IM or IV: 1 to 2 mcg/kg/dose; may repeat at 30 to 60 minute intervals. Note: Children 18 to 36 months of age may require 2 to 3 mcg/kg/dose.
--- Intranasal: Children greater than or equal to 10 kg: 1.5 mcg/kg once (maximum: 100 mcg/dose); reported range: 1 to 2 mcg/kg; some studies allowed for additional incremental doses of 0.5 mcg/kg to be administered every 5 minutes, not to exceed a total dose of 3 mcg/kg depending on pain type and severity.
---Continuous sedation/analgesia: Initial IV bolus: 1 to 2 mcg/kg then 1 mcg/kg/hour; titrate upward; usual: 1 to 3 mcg/kg/hour; some require 5 mcg/kg/hour
---Moderate to severe chronic pain: Transdermal patch: Opioid-tolerant children greater than or equal to 2 years receiving at least 60 mg oral morphine equivalents per day: Initial: 25 mcg/hour system or higher, based on conversion to fentanyl equivalents and administration of equianalgesic dosage (see package insert for further information); use short-acting analgesics for first 24 hours with supplemental PRN doses thereafter (for breakthrough pain); dose may be increased after 3 days, based on the daily dose of supplementary PRN opioids required; use the ratio of 45 mg of oral morphine equivalents per day to a 12.5 mcg/hour increase in transdermal patch dosage; change patch every 72 hours; Note: Dosing intervals less than every 72 hours are not recommended for children and adolescents. Initiation of the transdermal patch in children taking less than 60 mg of oral morphine equivalents per day has not been studied in controlled clinical trials; in open-label trials, children 2 to 18 years of age who were receiving at least 45 mg of oral morphine equivalents per day were started with an initial transdermal dose of 25 mcg/hour (or higher, depending upon equianalgesic dose of opioid received).

Children greater than or equal to 5 years and less than 50 kg:
Patient-controlled analgesia (PCA): IV: Opioid-naive: Note: PCA has been used in children as young as 5 years of age; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly. All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed.

Usual concentration: Determined by weight; some clinicians use the following:
---Children less than 12 kg: 10 mcg/mL
---Children 12 to 30 kg: 25 mcg/mL
---Children greater than 30 kg: 50 mcg/mL
---Demand dose: Usual initial: 0.5 to 1 mcg/kg/dose; usual range: 0.5 to 1 mcg/kg/dose
---Lockout: Usual initial: 5 doses/hour
---Lockout interval: Range: 6 to 8 minutes
---Usual basal rate: 0 to 0.5 mcg/kg/hour

Children greater than 12 years to adult:
Sedation for minor procedures/analgesia: IV: 0.5 to 1 mcg/kg/dose; may repeat after 30 to 60 minutes; or 25 to 50 mcg, repeat full dose in 5 minutes if needed, may repeat 4 to 5 times with 25 mcg at 5 minute intervals if needed. Note: Higher doses are used for major procedures.

Continuous sedation/analgesia:
---Less than 50 kg: Initial IV bolus: 1 to 2 mcg/kg; continuous infusion rate: 1 to 2 mcg/kg/hour
---Greater than 50 kg: Initial IV bolus: 1 to 2 mcg/kg or 25 to 100 mcg/dose; continuous infusion rate: 1 to 2 mcg/kg/hour or 25 to 200 mcg/hour

Patient-controlled analgesia (PCA): IV: Children greater than 50 kg, Adolescents greater than 50 kg, and Adults: Note: All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive. Assess patient and pain control at regular intervals and adjust settings if needed:

---Usual concentration: 50 mcg/mL
---Demand dose: Usual initial: 20 mcg; usual range: 10 to 50 mcg
---Lockout interval: Usual initial: 6 minutes; usual range: 5 to 8 minutes
---Usual basal rate: less than or equal to 50 mcg/hour

Preoperative sedation, adjunct to regional anesthesia, postoperative pain: IM, IV: 25 to 100 mcg/dose

Adjunct to general anesthesia: Slow IV:
---Low dose: 0.5 to 2 mcg/kg/dose depending on the indication
---Moderate dose: Initial: 2 to 20 mcg/kg/dose; Maintenance (bolus or infusion): 1 to 2 mcg/kg/hour. Discontinuing fentanyl infusion 30 to 60 minutes prior to the end of surgery will usually allow adequate ventilation upon emergence from anesthesia. For "fast-tracking" and early extubation following major surgery, total fentanyl doses are limited to 10 to 15 mcg/kg.
---High dose: 20 to 50 mcg/kg/dose; Note: High dose fentanyl as an adjunct to general anesthesia is rarely used, but is still described in the manufacturer label.

General anesthesia without additional anesthetic agents: IV: 50 to 100 mcg/kg with oxygen and skeletal muscle relaxant

Moderate to severe chronic pain: Transdermal patch: Opioid tolerant patients receiving at least 60 mg oral morphine equivalents per day: Initial: 25 mcg/hour system or higher, based on conversion to fentanyl equivalents and administration of equianalgesic dosage (see package insert for further information); use short-acting analgesics for first 24 hours with supplemental PRN doses thereafter (for breakthrough pain); dose may be increased after 3 days based on the daily dose of supplementary PRN opioids required; use the ratio of 45 mg of oral morphine equivalents per day to a 12.5 mcg/hour increase in transdermal patch dosage; transdermal patch is usually administered every 72 hours but select adult patients may require every 48-hour administration; dosage increase administered every 72 hours should be tried before 48-hour schedule is used.

Usual Pediatric Dose for Breakthrough Pain

TRANSMUCOSAL LOZENGE (Actiq(R))
Age 16 years or older:
-For use in patients who are opioid-tolerant and taking around-the-clock opioids. Opioid tolerant patients have been taking at least: morphine 60 mg daily, oral oxycodone 30 mg daily, oral hydromorphone 8 mg daily, or an equianalgesic dose of another opioid for 1 week or longer.
-Must be individually titrated to an effective and tolerable dose. Once titrated, treat up to 4 episodes of breakthrough pain a day; if a patient is experiencing more than 4 breakthrough episodes per day, the around-the-clock opioid dose should be re-evaluated. If the around-the-clock opioid dose is adjusted, re-adjustment of the transmucosal product may be necessary.
-Transmucosal fentanyl products are not bioequivalent; patients should not be interchanged on a mcg per mcg basis from 1 fentanyl product to any other fentanyl product

Initial dose: 200 mcg consumed over 15 minutes
Dose titration: If breakthrough pain is not relieved 15 minutes after completion of 1 unit (30 minutes after start), 1 additional unit of the same strength may be taken; Patients must wait at least 4 hours before re-treating. If breakthrough pain had not been relieved with 1 unit, the dose should be increased to the next highest strength with subsequent episodes of pain.
Maintenance dose: An effective dose is achieved when 1 unit is mostly sufficient to treat an episode of breakthrough pain; however, if there is inadequate analgesia a second dose of the same strength may be given 15 minutes after completion (30 minutes after start); no more than 2 doses should be used to treat any episode of breakthrough pain.
Maximum dose: 4 breakthrough episodes per day at intervals of at least 4 hours

Comments: The lozenge should be placed in mouth between cheek and lower gum and sucked; occasionally move from side to side using the handle; do not chew.
-If signs of excessive opioid effects appear before the unit is consumed, the unit should be removed immediately and subsequent doses should be decreased.

Use: For the management of breakthrough pain in adolescents 16 years or older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain.

Renal Dose Adjustments

Transdermal patches:
Mild to moderate renal impairment: Start with one half of the usual dosage
Severe renal impairment: Avoid use

No specific dose adjustment guidelines for other dose forms have been suggested; however, caution is advised along with observation and dose reduction if indicated.

Liver Dose Adjustments

Transdermal patches:
Mild to moderate hepatic impairment: Start with one half of the usual dosage
Severe hepatic impairment: Avoid use

No specific dose adjustment guidelines for other dose forms have been suggested; however, caution is advised along with observation and dose reduction if indicated.

Dose Adjustments

-Different dose forms of this drug are not bioequivalent. Patients should not be converted on a mcg per mcg basis from other dose forms. Product labeling or local protocol should be consulted when switching patients from one dose form to another.
-Elderly patients may be more sensitive to the effects of fentanyl than younger patients. Close monitoring and a reduced dosage should be considered in elderly and debilitated patients.
-When discontinuing fentanyl transdermal system and not converting to another opioid, use a gradual downward titration, such as halving the dose every 6 days, in order to reduce the possibility of withdrawal symptoms.
-Consult the most current therapeutic guidelines and/or the manufacturer product information for dosing recommendations.

CYP450 3A4 Inhibitors and Inducers: Increased fentanyl plasma concentrations may result from concomitant use with CYP450 3A4 inhibitors or discontinuation of concomitantly used CYP450 3A4 inducers; monitor patients concomitantly receiving any CYP450 3A4 inducers or inhibitors and make dose adjustments as appropriate.

Concomitant use with other CNS depressants, including other opioids, sedative or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects; monitor patients receiving concomitant CNS depressants and consider adjusting fentanyl dose.

Initial Dose Recommendations for Patients on Transmucosal Lozenges (Actiq(R)):
-For patients with a current fentanyl transmucosal lozenge dose of 200 mcg, initiate fentanyl sublingual tablets (Abstral(R)) at 100 mcg; for a current transmucosal lozenge dose of 400 mcg, 600 mcg, 800 mcg, or 1200 mcg, initiate sublingual tablets at 200 mcg; for a current transmucosal lozenge dose of 1600 mcg, initiate sublingual tablets at 400 mcg; proceed with titration outlined in the dosing section.
-For patients with a current fentanyl transmucosal lozenge of 200 mcg or 400 mcg, initiate fentanyl buccal dose (Fentoral(R)) at 100 mcg; for a current transmucosal lozenge dose of 600 mcg or 800 mcg, initiate buccal tablet at 200 mcg; for a current transmucosal lozenge dose of 1200 mcg or 1600 mcg, initiate buccal dose at 400 mcg (2x200 mcg) ; proceed with titration outlined in the dosing section.
-For patients with a current fentanyl transmucosal lozenge of 200 mcg or 400 mcg, initiate fentanyl sublingual spray (Subsys(R)) at 100 mcg; for a current transmucosal lozenge dose of 600 mcg or 800 mcg, initiate sublingual spray at 200 mcg; for a current transmucosal lozenge dose of 1200 mcg or 1600 mcg, initiate sublingual spray at 400 mcg; proceed with titration outlined in the dosing section.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for:
-Fentanyl Iontophoretic Transdermal System (Ionsys(R)); it includes elements to assure safe use and an implementation system.
-Transmucosal Immediate-Release Fentanyl Products (sublingual tablets, oral lozenges, buccal tablets, nasal spray, and sublingual spray); it includes a medication guide, elements to assure safe use, and an implementation system.
-Transdermal Fentanyl Systems (shared system for extended-release and long-acting opioid analgesics); it includes a medication guide and elements to assure safe use.
Additional information is available at www.fda.gov/Drugs/DrugSafety/postmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm.

US BOXED WARNINGS: Iontophoretic Transdermal Systems
- LIFE-THREATENING RESPIRATORY DEPRESSION; Use may result in potentially life-threatening respiratory depression and death as a result of the active drug fentanyl. Only the patient should activate dosing. Accidental exposure to an intact transdermal system or to the hydrogel component, especially by children, through contact with skin or contact with mucous membranes, can result in a fatal overdose of fentanyl. This system is only for use in hospitalized patients; treatment should be discontinued before patient leaves the hospital.
-ADDICTION, ABUSE, and MISUSE: This drug exposes 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 monitor regularly for the development of these behaviors or conditions.
ACCIDENTAL EXPOSURE: Because of the risk of life-threatening respiratory depression resulting from accidental exposure, this drug is available only through a restricted REMS program.
-CYP450 3A4 INTERACTION: Concomitant use with CYP450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Additionally, discontinuation of a concomitantly used CYP450 3A4 inducer may result in an increase in fentanyl plasma concentrations. Monitor patients concomitantly receiving any CYP450 3A4 inhibitor or inducer.

US BOXED WARNINGS: Transmucosal Immediate-Release Fentanyl (TIRF) Products (sublingual and buccal tablets, transmucosal lozenges, nasal and sublingual spray)
-RESPIRATORY DEPRESSION: Fatal respiratory depression has occurred in patients treated with immediate-release transmucosal fentanyl, including following used in opioid non-tolerant patients and improper dosing. The interchange of one TIRF product for any other fentanyl product may result in fatal overdose. Due to the risk of respiratory depression, TIRF products are contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. Keep out of reach of children. Concomitant use with CYP450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression.
-MEDICATION ERRORS: Substantial differences exist in the pharmacokinetic profile of fentanyl products that may result in clinically important differences in the extent of absorption and possible fatal overdose. When prescribing, do not convert patients on a mcg per mcg basis; when dispensing, do not substitute TIRF for each other or other fentanyl products.
-ABUSE POTENTIAL: Fentanyl is a schedule II controlled substance, with an abuse liability similar to other opioid analgesics, legal or illicit. Physicians or pharmacists should consider the risk of misuse, abuse or diversion when prescribing or dispensing. Healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the TIRF REMS Access program.

US BOXED WARNINGS: Transdermal Systems
-ADDICTION, ABUSE, and MISUSE: The drug 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 monitor regularly for the development of these behaviors or conditions.
-LIFE-THREATENING RESPIRATORY DEPRESSION: Serious, life-threatening, or fatal respiratory depression may occur, even when used as recommended. Monitor for respiratory depression, especially during initiation and following dose increases. Because of the risk of respiratory depression, this drug is contraindicated for use as an as-needed analgesic, in non-opioid tolerant patients, in acute pain, and in postoperative pain.
-ACCIDENTAL EXPOSURE: Deaths due to fatal overdose of this drug have occurred due to accidental exposure. Strict adherence to the recommended handling and disposal instructions is of the utmost importance to prevent accidental exposure.
-NEONATAL OPIOID WITHDRAWAL SYNDROME: Prolonged use of this drug during pregnancy may result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
-CYP450 3A4 INTERACTION: Concomitant use with CYP450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Additionally, discontinuation of a concomitantly used CYP450 3A4 inducer may result in an increase in fentanyl plasma concentrations. Monitor all patients concomitantly receiving any CYP450 3A4 inhibitor or inducer.
-HEAT EXPOSURE: Exposure of the application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, sunbathing, hot baths, saunas, hot tubs, and heated water beds may increase drug absorption and has resulted in fatal overdose and death. Patients wearing transdermal systems who develop fever or increased core body temperature due to strenuous exertion are also at risk for increased drug exposure and may require dose adjustment to avoid overdose and death.

-Iontophoretic transdermal system, Buccal tablets, Nasal spray, and Sublingual tablets and spray: Safety and efficacy have not been established in patients younger than 18 years.
-Oral transmucosal lozenge: Safety and efficacy have not been established in patients younger than 16 years.
-Parenteral and Transdermal systems: Safety and efficacy have not been established in patients younger than 2 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule II

Dialysis

Data not available

Other Comments

Administration Advice:
Parenteral administration:
-May be administered by slow IV infusion (over 1 to 2 minutes) or IM injection.

Transdermal patch:
-Patches should be worn continuously for 72 hours.
-Patches should be applied to non-irritated, and non-irradiated skin on the torso or upper arms.
-A non-hairy application site is preferred; however, hair may be clipped (not shaven) prior to application.
-The application site may be cleaned with water and should be dry prior to application; soaps, oils, lotions, or other agents that may irritate or alter the characteristics of the skin should not be used.
-The patch should be applied immediately after removal from the sealed package; press firmly in place for 30 seconds.
-Application sites should be rotated.
-If there is a problem with adhesion, the edges may be taped with first aid tape; if the problem persists, overlay the patch with a transparent adhesive film dressing.
-If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet; apply a new patch to a different skin site.
-Anyone handling the patch should wash their hands immediately with soap and water.

Transmucosal lozenge:
-Once titrated to an effective dose, patients should generally consume 1 unit for each episode of breakthrough pain; occasionally, an additional unit of the same strength may be taken if analgesia is inadequate after 15 minutes (30 minutes from start of dosing); at least 4 hours must elapse before treating a new episode; a maximum of 2 doses may be used for each episode of breakthrough pain.
-Open the blister package with scissors immediately prior to use; place lozenge in the mouth against the cheek and lower gum.
-Move lozenge around using the applicator provided over a 15 minute period, longer or shorter consumption may affect efficacy; the lozenge should be sucked and not chewed.
-If any of the drug matrix remains on the handle, place the handle under hot running water until it is dissolved and then dispose of out of the reach of children.

Sublingual tablets:
-Once titrated to an effective dose, patients should generally take 1 dose for each episode of breakthrough pain; occasionally, an additional dose of the same strength may be taken 30 minutes later if analgesia is inadequate; at least 2 hours must elapse before treating a new episode; a maximum of 2 doses may be used for each episode of breakthrough pain.
-Immediately after removal from blister, place tablet underneath the deepest part of the tongue; allow tablet to complete dissolve in the sublingual space without chewing or sucking.
-Patients should not eat and drink until after the tablet has completely dissolved.
-In patients who have a dry mouth, water may be used to moisten the mouth prior to administration.

Sublingual spray:
-Once titrated to an effective dose, patients should generally take 1 dose for each episode of breakthrough pain; 1 additional dose of the same strength may be taken 30 minutes later if analgesia is inadequate; at least 4 hours must elapse before treating a new episode; a maximum of 2 doses may be used for each episode of breakthrough pain.
-Open the blister pack with scissors immediately prior to use; carefully spray dose into mouth under the tongue.

Nasal spray:
-No more than 1 dose should be taken for each episode of breakthrough pain and at least 2 hours must elapse before treating a new episode.
-To prime the bottle for initial use, firmly press down 4 times on the finger grips; with each press, a click should be heard, after 4 clicks a green bar should appear in the counting window and the bottle is ready.
-Re-priming will be necessary if the bottle is not used for more than 5 days; to re-prime, spray 1 time into the pouch.
-To administer, patients should sit or stand in an upright position, insert the tip a short distance into nose and point the tip toward the bridge of nose, this will tilt the bottle slightly.
-Close off the other nostril with 1 finger; firmly press down on the finger grips until a click is heard, and breathe in gently through nose and out through mouth 1 time after spraying; do not sniff after spraying.
-It is normal not to feel the spray go into the nose, after the click, the number in the counting window should increase by 1 and this indicates that a spray has been given.
-If more than 1 spray is needed, repeat process alternating nostrils; the maximum number of sprays that may be used to be treat an episode of breakthrough pain is 4 (2 sprays in each nostril, alternating, e.g., right, left, right, left).
-Patient should remain upright, preferably sitting for 1 minute after using spray.
-Avoid blowing nose for at least 30 minutes after each spray.

Buccal tablets:
-Once titrated to an effective dose, patients should generally take 1 dose for each episode of breakthrough pain; 1 additional dose of the same strength may be taken 30 minutes later if analgesia is inadequate; at least 4 hours must elapse before treating a new episode; a maximum of 2 doses may be used for each episode of breakthrough pain.
-Peel back blister and remove tablet, do not push tablet through blister as this may damage the tablet.
-Immediately after removing tablet from blister, place tablet in buccal cavity (above a rear molar between upper cheek and gum).
-Leave in buccal cavity for 14 to 25 minutes or until the tablet has dissolved; if after 30 minutes remnants of the tablet remain, these may be swallowed with some water.
-Food should not be consumed while tablet is in buccal cavity.
-The tablet should not be split, sucked, chewed, or swallowed whole; patients should alternate sides of the mouth when administering subsequent doses.
-Alternatively, the buccal tablet may be placed under the tongue (sublingually).

Iontophoretic Transdermal System
-For hospital use only and only for use in patients who are alert enough and have adequate ability to understand the directions for use; discontinue treatment before patient leaves the hospital.
-Anyone handling the unit should wear gloves; assemble and use immediately after removal from the individually sealed package.
-Apply system to healthy, unbroken/intact, non-irritated, and non-irradiated skin on the chest or upper outer arms; clip excessive hair if necessary, do not shave as this may irritate skin.
-Clean site with alcohol and let dry; do not use soaps, lotions, or other agents.
-Only the patient should self-administer doses; a healthcare professional should observe the first dose to ensure the patient understands how to operate the system and that the system is working properly.
-To initiate administration, press and release the recessed button on the top housing of the unit twice within 3 seconds, a single audible beep indicates the delivery of the dose has begun; the green light will start blinking rapidly and the digital display will alternate between a walking circle and number of doses delivered.
-After 10 minutes, the green light will blink slowly and the display will show the number of doses delivered; at this time the unit is ready to be used again; pressing the button during delivery of a dose will not result in additional drug being administered.

Storage requirements: KEEP OUT OF THE REACH OF CHILDREN
-Store at 20 to 25C (68F to 77F); excursions permitted between 15C and 30C (59F to 86F).
-Parenteral products: Protect from light
-Transdermal Patches: Store in original pouches
-Sublingual tablets: Store in original blister unit
-Transmucosal Lozenges: Store in original blister package; protect from freezing and moisture; may obtain a Child Safety Kit from manufacturer
-Nasal Spray: Store at up to 25C; do not freeze; return bottle to child-resistant container after each use; put pouch in cardboard carton and store securely; protect from light
-Buccal tablets: Store in original blister package; protect from freezing and moisture
-Sublingual Spray: Store in original blister package; may obtain a Child Safety Kit from manufacturer.
Iontophoretic transdermal system: Store in individually sealed package

Preparation and Disposal:
-The individual manufacturer product information should be consulted for complete information on preparation and disposal.

IV compatibility:
-Fentanyl solution for injection is incompatible with thiopental sodium and methohexital sodium

General:
-This drug should be prescribed by healthcare professional who are knowledgeable in the use of potent opioids.
-Except for the parenteral product, patients should be opioid tolerant prior to initiating therapy; patients receiving transmucosal products for breakthrough pain should be receiving around-the-clock opioid pain medication.
-Switching between fentanyl products should not occur at 1:1 ratio as fentanyl products are not bioequivalent.
-For patients receiving other opioid analgesics and switching to this drug, it is safer to underestimate a patient's 24-hour oral requirement and provide rescue medication than overestimate and manage an adverse reaction; there is substantial inter-patient variation in the relative potency of different opioid drugs that conversion tables are not able to capture.
-During chronic therapy, periodically reassess the continued need for opioid analgesics.
-The iontophoretic transdermal system contains metal parts and therefore must be removed prior an MRI procedure; this device can be damaged by strong electromagnetic fields and should be removed prior to cardioversion, defibrillation, diathermy, and radiographic imaging procedures (X-ray or CT scan).

Monitoring:
-Monitor regularly for the development of addiction, abuse, and misuse.
-Respiratory: Monitor closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dose increases.
-Cardiovascular: Monitor at risk patients for signs of hypotension on initiation and with each dose titration; monitor patients with bradyarrhythmias for changes in heart rate, particularly upon drug initiation.
Gastrointestinal: Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Nervous System: Monitor for signs of sedation and respiratory depression in patients who may be susceptible; monitor patients with a history of seizures for worsened seizure control.
Renal/Hepatic impairment: Monitor for fentanyl toxicity
-Transdermal Patch: Monitor febrile patients closely for fentanyl toxicity

Patient advice:
-This drug should be stored safely out of the sight and reach of children; accidental use by a child is a medical emergency and can result in death.
-Taking this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect their drug from theft or misuse.
-Patients should understand the risks of life-threatening respiratory depression, and be informed as to when this risk is greatest.
-This drug may cause drowsiness, dizziness, impaired thinking and/or motor skills; patients should be aware of these dangers and avoid driving or other potentially dangerous tasks while taking this drug.
-Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.
-Patients should be instructed in proper disposal .

Fentanyl Side Effects