FENTANYL JANSSEN

Injection, USP, is an opioid agonist, available as a sterile, non-pyrogenic solution containing fentanyl citrate as the active pharmaceutical ingredient, for intravenous or intramuscular administration.

Fentanyl citrate is chemically identified as

N -(1-Phenethyl-4-piperidyl)propionanilide citrate (1:1) with the following structural formula: C 22 H 28 N 2 O.

• C 6 H 8 O 7 Molecular Weight is 528.59 Each mL contains fentanyl citrate equivalent to 50 mcg fentanyl base in Water for Injection.

Sodium hydroxide and/or hydrochloric acid added, if needed, for pH adjustment.

The pH range is 4.0 to 7.5.

Contains no preservative. fenta-struc-01.jpg.

Fentanyl is a central analgesic for short, medium or long-term anesthesia.

• neuroleptanalgesia, general swing anesthesia, analgesic anesthesia at high doses.

• in post-operative analgesia exclusively in patients under intensive medical supervision (i.e. intensive care unit, wake-up room),.

• by peridural route, either in isolation or in combination with local anesthetics.

The use of a drug is not controlled by the drug.

Injection is an opioid agonist, whose principal actions of therapeutic value are analgesia and sedation. 12.2 Pharmacodynamics Effects on the Central Nervous System 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 respiratory centers to both increases in carbon dioxide tension and 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 origins may produce similar findings).

Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum.

Digestion of food in the small intestine is delayed 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 biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Fentanyl produces peripheral vasodilation which may result in orthostatic hypotension or syncope.

Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans.

They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models.

The clinical significance of these findings is unknown.

Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration – Efficacy Relationships A dose of 100 mcg of Fentanyl Citrate Injection is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of meperidine.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists.

The minimum effective analgesic concentration of fentanyl for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance.

The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, the maximal analgesic effect may not be noted for several minutes.

The usual duration of action of the analgesic effect is to 60 minutes after a single intravenous dose of up to 100 mcg. Following intramuscular administration, the onset of action is from seven to eight minutes, and the duration of action is one to two hours.

Concentration – Adverse Reaction Relationships There is a relationship between increasing fentanyl plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, the maximal respiratory depressant effect may not be noted for several minutes.

As with longer acting narcotic analgesics, the duration of the respiratory depressant effect of fentanyl may be longer than the analgesic effect.

• Diminished sensitivity to CO 2 stimulation may persist longer than depression of respiratory rate. (Altered sensitivity to CO 2 stimulation has been demonstrated for up to four hours following a single dose of 600 mcg fentanyl to healthy volunteers). Fentanyl frequently slows the respiratory rate, duration and degree of respiratory depression being dose related.

• The peak respiratory depressant effect of a single intravenous dose of fentanyl citrate is noted to 15 minutes following injection. 12.3 Pharmacokinetics Fentanyl Citrate Injection is administered by the intravenous or intramuscular route.

The pharmacokinetics of fentanyl can be described as a three-compartment model.

Fentanyl plasma protein binding capacity increases with increasing ionization of the drug.

Alterations in pH may affect its distribution between plasma and the central nervous system.

It accumulates in skeletal muscle and fat and is released slowly into the blood.

The volume of distribution for fentanyl is 4 L/kg. It has a distribution time of 1.7 minutes and redistribution time of 13 minutes.

The terminal elimination half-life is 219 minutes.

Fentanyl, which is primarily transformed in the liver, demonstrates a high first pass clearance and releases approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 10% representing the unchanged drug.

Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

Pharmacotherapeutic group

General anesthetics, opioid anesthetics, ATC code: N01AH01 Fentanyl is a synthetic opioid with the pharmacological properties of an agonist of the μ receptors.

Fentanyl is a major analgesic.

It is a very potent morphinomimetic that causes surgical analgesia about 50-100 times higher than that of morphine in humans.

Intravenous administration, its onset of action occurs in 2-3 minutes and its effect persists approximately 30 minutes at a dose of 1-2 μg/kg.

All effects associated with activation of morphine receptors are suppressed by the use of a specific opioid antagonist.

Fentanyl is compatible with agents usually used in anesthesia: other analgesics, general and local anesthetics, neuroleptics, tranquillisers, curares, ganglioplegs and vasomotive substances.

The safety of fentanyl

Intravenous was evaluated in 376 subjects treated with fentanyl Intravenous used as anaesthetic in 20 clinical trials, and these subjects received at least one dose of fentanyl Intravenous.

Based on the safety data from these clinical studies, the most frequently reported adverse reactions (incidence ≥ 5%) were: nausea (26.1%), vomiting (18.6%), muscle stiffness (10.4%), hypotension (8.8%), hypertension (8.8%), bradycardia (6.1%) and sedation (5.3%).

These adverse reactions are included in the table below, which describes the adverse reactions reported with fentanyl Intravenous either in clinical studies or after marketing.

The frequencies are defined as follows: very common (≥ 1/10), frequent (≥ 1/100 to < 1/10), low frequency (≥ 1/1000 to < 1/100) and unknown (frequency cannot be estimated from the data available in clinical trials).

Acute overdose with fentanyl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death.

Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated.

Cardiac arrest or arrhythmias will require advanced life-support measures.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose.

For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in Fentanyl Citrate Injection, carefully monitor the patient until spontaneous respiration is reliably re-established.

If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome.

The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered.

If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

• 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.