PECFENT

Fentanyl, a potent opioid agonist, was developed in the 1950s to fill a need for strong and rapid analgesia.

Because of these characteristics, fentanyl is commonly used to treat chronic cancer pain or in anesthesia.

Label, 15, 16, 17, 18, 19, 20, 21 Fentanyl is related to other opioids like morphine and oxycodone.

Fentanyl's high potency has also made it a common adulterant in illicit drugs, especially heroin.

In 2017, 47600 overdose deaths in the United States involved some opioid (over 2/3 of all overdose deaths).

Opioid overdoses kill an average of 11 Canadians daily.

Fentanyl was

FDA approved in 1968.

Label, 15, 16, 17, 18, 19, 20, 21.

Fentanyl intravenous or intramuscular injections are indicated for short term analgesia during induction, maintenance, and recovery from general or regional anesthesia.

These injections are also used with a neuroleptic for premedication, induction, and as an adjunct to maintenance of anesthesia.

Finally, fentanyl intravenous or intramuscular injections are used with oxygen for anesthesia in high risk patients.

Fentanyl sublingual tablets, transmucosal lozenges, buccal tablets, sublingual sprays, transdermal systems, and nasal sprays are indicated for the management of breakthrough pain in opioid tolerant cancer patients who require around the clock pain management. 15, 16, 17, 18, 19,

Fentanyl produces strong analgesia through its activation of opioid receptors.

Label, 6 It has a duration of action of several hours and a wider therapeutic index as patients develop tolerance to opioids.

Fentanyl is associated with a risk of addiction and abuse and should not be mixed with alcohol or benzodiazepines.

Label, 15, 16, 17, 18, 19, 20, 21.

Fentanyl sublingual tablets are 54% bioavailable 15, transmucosal lozenges are 50% bioavailable 16, buccal tablets are 65% bioavailable 17, sublingual spray is 76% bioavailable 18, and nasal spray is 20% more bioavailable than transmucosal 20 (or approximately 64% bioavailable).

Fentanyl transmucosal lozenges reach a

C max of 0.4±0.1ng/mL for a 200 µg dose and 2.5±0.6ng/mL for a 1600 µg dose with a T max of 20-40 minutes.

AUC was 172±96ngmin/mL for a 200 µg dose and 1508±1360ngmin/mL for a 1600 µg dose.

Fentanyl sublingual spray reached a

C max of 0.20±0.06ng/mL for a 100 µg dose and 1.61±0.60ng/mL for an 800 µg dose with a T max of 0.69-1.25 hours, decreasing as the dose increased.

AUC was 1.25±0.67ngh/mL for a 100 µg dose and 10.38±3.70ngh/mL for a 800 µg dose.

Fentanyl transdermal systems reached a

C max of 0.24±0.20ng/mL with a T max of 3.6±1.3h for a 25 µg/h dose.

AUC was 0.42±0.35ng/mL*h.

Fentanyl nasal spray reaches a

C max of 815±301pg/mL with a T max of less than 1 hour for a 200 µg/100µL dose.

AUC was 3772pg*h/mL.

The intravenous volume of distribution is 4 L/kg (3-8 L/kg) Label, 19.

The oral volume of distribution is 25.4 L/kg.

In hepatically impaired patients, the intravenous volume of distribution ranges from 0.8-8 L/kg.

Fentanyl crosses the blood brain barrier and the placenta.

Fentanyl is metabolized to a number of inactive metabolites.

Fentanyl is 99% N-dealkylated to norfentanyl by cytochrome P450.

It can also be amide hydrolyzed to despropionylfentanyl, or alkyl hydroxylated to hydroxyfentanyl which is N-dealkylated to hydroxynorfentanyl.

Hover over products below to view reaction partners Fentanyl norfentanyl Despropionylfentanyl Hydroxyfentanyl Hydroxynorfentanyl.

Within 72 hours, 75% of a dose of fentanyl is excreted in the urine with <7% unchanged, and 9% is excreted in the feces with <1% unchanged.

The half life of fentanyl is 7 hours.

The half life of fentanyl sublingual spray is 5-12 hours.

Total plasma clearance of fentanyl is 0.5 L/hr/kg (0.3-0.7 L/hr/kg) 16 or 42 L/hr. 17, 20 Following an intravenous dose, surgical patients displayed a clearance of 27-75 L/h, hepatically impaired patients displayed a clearance of 3-80 L/h, and renally impaired patients displayed a clearance of 30-78 L/h.

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Fentanyl has an intravenous

LD of 2.91 mg/kg in rats 1, an oral LD of 18 mg/kg in rats and 368 mg/kg in mice.

LD50 in humans is not known.

Symptoms of overdose include respiratory depression, somnolence, stupor, coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction, pulmonary edema, bradycardia, hypotension, airway obstruction, atypical snoring, and death.

Label, 15, 16, 17, 18, 19, 20 In case of overdose, patients should receive naloxone or nalmefene to reverse the action of the opioids as well as supportive measures to maintain the airway or advanced life support in the case of cardiac arrest.

Label, 15, 16, 17, 18, 19, 20.

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

• Hypersensitivity to fentanyl.

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

• Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available.

• Individualize dosing based on the factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.

• Initiate treatment in adults with 50 mcg to 100 mcg.

• Initiate treatment in children to 12 years of age, with a reduced dose as low as 2 mcg/kg to 3 mcg/kg. 2.1 Important Dosage and Administration Instructions Fentanyl Citrate Injection should be administered only by persons specifically trained in the use of intravenous anesthetics and management of the respiratory effects of potent opioids.

• Individualize dosage based on factors such as age, body weight, physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used, and the surgical procedure involved.

• Monitor vital signs routinely.

As with other potent opioids, the respiratory depressant effect of fentanyl may persist longer than the measured analgesic effect.

The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

If Fentanyl Citrate Injection is administered with a CNS depressant, become familiar with the properties of each drug, particularly each product's duration of action.

In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.2 Dosage Premedication in Adults 50 mcg to 100 mcg may be administered intramuscularly to 60 minutes prior to surgery.

Adjunct to General Anesthesia See Dosage Range Charts below.

Table 1: Dosage Range Chart Total Dosage (expressed as fentanyl base) Low Dose —2 mcg/kg For use in minor, but painful, surgical procedures.

May also provide some pain relief in the immediate postoperative period.

Dose —2 mcg/kg to 20 mcg/kg For use in more major surgical procedures, in addition to adequate analgesia, may abolish some of the stress response.

Expect respiratory depression requiring artificial ventilation during anesthesia and careful observation of ventilation postoperatively is essential.

High dose —20 mcg/kg to 50 mcg/kg For open heart surgery and certain more complicated neurosurgical and orthopedic procedures where surgery is more prolonged, and the stress response to surgery would be detrimental to the well-being of the patient.

In conjunction with nitrous oxide/oxygen has been shown to attenuate the stress response as defined by increased levels of circulating growth hormone, catecholamine, ADH and prolactin.

Expect the need of postoperative ventilation and observation due to extended post-operative respiratory depression.

Dose (expressed as fentanyl base) Low Dose —2 mcg/kg Additional dosages infrequently needed in these minor procedures.

Dose —2 mcg/kg to 20 mcg/kg 25 mcg to 100 mcg Administer intravenously or intramuscularly as needed when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia.

Dose —20 mcg/kg to 50 mcg/kg Maintenance dosage [ranging from 25 mcg to one half the initial loading dose] as needed based on vital signs indicative of stress and lightening of analgesia.

Individualize the dosage especially if the anticipated remaining operative time is short.

Anesthesia 50 mcg to 100 mcg may be administered intramuscularly or slowly intravenously, over one to two minutes, when additional analgesia is required.

Postoperatively (recovery room) 50 mcg to 100 mcg may be administered intramuscularly for the control of pain, tachypnea and emergence delirium.

The dose may be repeated in one to two hours as needed.

For Induction and Maintenance in

Children to 12 Years of Age A reduced dose as low as 2 mcg/kg to 3 mcg/kg is recommended.

As a technique to attenuate the responses to surgical stress without the use of additional anesthetic agents, doses of 50 mcg/kg to 100 mcg/kg may be administered with oxygen and a muscle relaxant.

In certain cases, doses up to 150 mcg/kg may be necessary to produce this anesthetic effect.

It has been used for open heart surgery and certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen demand is particularly indicated, and for certain complicated neurological and orthopedic procedures. 2.3 Instructions for Use of Fentanyl Citrate Injection Prefilled Syringe INSTRUCTIONS FOR USE – MicroVault ® Figure 1: Outer Packaging (MicroVault ® ) and Prefilled Syringe NOTES:

• Do not introduce any other fluid into the syringe at any time.

• Do not dilute for IV push.

• Do not re-sterilize the syringe.

• Do not use this product on a sterile field.

• This product is for single dose only. 1.

• Integrity of the tube and the cap.

• Tamper evident seal is intact (outer shrink wrap is not broken).

Do not use if the outer packaging has been damaged. 2.

Hold the outer packaging with both hands.

To break the tamper evident seal, hold the tube and the cap close to the seal, and twist until broken.

Figure 2 3.

Remove the cap of the outer packaging by pulling it straight away from the tube to avoid dislodging the plunger rod of the syringe.

Figure 3 4.

Remove the syringe from the tube. 5.

Visually inspect the syringe.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 6.

Twist off the syringe tip cap.

Do not remove the plastic wrap label around the luer lock collar.

Figure 4 7.

Expel air bubble(s).

Adjust the dose (if applicable). 8.

Administer the dose ensuring that pressure is maintained on the plunger rod during the entire administration. 9.

Discard the used syringe into an appropriate receptacle.

For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176.

USE – Blister Pack Figure 1: Outer Packaging and Prefilled Syringe NOTES:

Inspect the outer packaging (blister pack) to confirm the integrity of the packaging.

Do not use if the blister pack or the prefilled syringe has been damaged. 2.

Remove the syringe from the outer packaging.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 4.

Do not remove the label around the luer lock collar.

Figure 3 5.

Expel air bubble (s).

Adjust the dose (if applicable). 6.

Administer the dose ensuring that pressure is maintained on the plunger rod during the entire administration. 7.

For more information concerning this drug, please call Fresenius Kabi USA, LLC at 1-800-551-7176. fenta-fig-05.jpg fenta-fig-06.jpg fenta-fig-07.jpg fenta-fig-01.jpg fenta-fig-02.jpg fenta-fig-03.jpg fenta-fig-04.jpg.

Injection, USP, is supplied as a sterile, clear, and colorless solution.

Injection, USP, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, supplied as follows: Product Code Unit of Sale Strength Each 806711 NDC 63323-808-11 Unit of 10 (Micro Vault ® ) 50 mcg/mL NDC 63323-808-01 1 mL Single-Dose Prefilled Syringe 806722 NDC 63323-810-20 Unit of 20 100 mcg/2 mL (50 mcg/mL) NDC 63323-810-00 2 mL Single-Dose Prefilled Syringe PROTECT FROM LIGHT.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) .

Contains no preservative.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.fda.gov/medwatch.

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.

Available data with Fentanyl Citrate

Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes.

There are adverse outcomes reported with fetal exposure to opioid analgesics.

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing.

No evidence of malformations was noted in animal studies completed to date.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight.

The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

There are insufficient data to support the use of fentanyl in labor or delivery.

Therefore, such use is not recommended.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.

An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.

Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.

Opioid analgesics, including Fentanyl Citrate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Fentanyl has been shown to be embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on a mg/m 2 basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100 mcg/kg on a mg/m 2 basis).

There was no evidence of teratogenicity reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy.

The high dose was approximately 0.81 times the human dose of 100 mcg/kg on a mg/m 2 basis.

The safety and efficacy of Fentanyl Citrate Injection in pediatric patients under two years of age has not been established.

Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included combined use of fentanyl, pancuronium and atropine.

A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

Elderly patients (aged 65 years or older) may have increased sensitivity to fentanyl.

In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

Titrate the dosage of Fentanyl Citrate

Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression.

Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.