Fentanyl Citrate: Package Insert and Label Information

FENTANYL CITRATE- fentanyl citrate injection
Hikma Pharmaceuticals USA Inc.

1 INDICATIONS AND USAGE

Fentanyl Citrate Injection is indicated for:

• analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises.
• use as a narcotic analgesic supplement in general or regional anesthesia.
• administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.
• use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures.

2 DOSAGE AND ADMINISTRATION

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.

• Ensure that an opioid antagonist, resuscitative and intubation equipment, and oxygen are readily available.
• 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 [see Warnings and Precautions (5.4)].

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 to 100 mcg may be administered intramuscularly 30 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.

Moderate 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.

Maintenance Dose (expressed as fentanyl base)

Low Dose —2 mcg/kg Additional dosages infrequently needed in these minor procedures.

Moderate 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.

High 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.

Adjunct to Regional 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 2 to 12 Years of Age

A reduced dose as low as 2 mcg/kg to 3 mcg/kg is recommended.

As a General Anesthetic

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

CAUTION: Glass syringes may malfunction, break or clog when connected to some Needleless Luer Access Devices (NLADs) and needles. The external collar must remain attached to the syringe (See Figure 1). Spontaneous disconnection of this glass syringe from needles and NLADs with leakage of drug product may occur. Assure that the needle or NLAD is securely attached before beginning the injection. Inspect the glass syringe-needle or glass syringe-NLAD connection before and during administration.

Figure 1

1. Inspect the integrity of the plastic tube, cap and tamper evident seal. Do not use if the tamper evident seal has been damaged.
2. Break the tamper evident seal when removing the cap to access the syringe.

3. Push plunger rod slightly to break the stopper loose while tip cap is still on.

4. Remove tip cap by twisting it off. (See Figure 2)

Figure 2

5. Connect the syringe to an appropriate injection connection.

6. Depress plunger rod to deliver the required dose.

3 DOSAGE FORMS AND STRENGTHS

Single-Dose Ampuls, Vials and Prefilled Syringes:

Fentanyl Citrate Injection, USP, equivalent to 50 mcg fentanyl base per mL, is a preservative-free solution, available in 2 mL, 5 mL, 20 mL single-dose glass ampuls and 1 mL, 2 mL, 5 mL, 20 mL, 50 mL single-dose glass vials and 0.5 mL and 1 mL single-dose, prefilled, glass syringes.

4 CONTRAINDICATIONS

Fentanyl Citrate Injection is contraindicated in patients with:

• Hypersensitivity to fentanyl (e.g., anaphylaxis) [See Adverse Reactions (6)]

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled substance. As an opioid, Fentanyl Citrate Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Opioids are sought by drug users and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling Fentanyl Citrate Injection. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Fentanyl Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO₂ ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential. As with other potent opioids, the respiratory depressant effect of Fentanyl Citrate Injection may persist longer than the measured analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before ordering opioid analgesics during recovery from anesthesia.

Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics can alter respiration by blocking intercostal nerves. Through other mechanisms [see Clinical Pharmacology (12.2)] Fentanyl Citrate Injection can also alter respiration. Therefore, when Fentanyl Citrate Injection is used to supplement these forms of anesthesia, the anesthetist should be familiar with the physiological alterations involved, and be prepared to manage them in the patients selected for these forms of anesthesia.

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Fentanyl Citrate Injection. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression.

Monitor such patients closely including vital signs, particularly when initiating and titrating Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of Fentanyl Citrate Injection are essential [see Dosage and Administration (2.1)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.1)].

5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Fentanyl Citrate Injection with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may exacerbate respiratory depression [see Warnings and Precautions (5.2)] , particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Fentanyl Citrate Injection-treated patients may increase fentanyl plasma concentrations and prolong opioid adverse reactions. When using Fentanyl Citrate Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Fentanyl Citrate Injection-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Fentanyl Citrate Injection [see Dosage and Administration (2.1), Drug Interactions (7)].

Concomitant use of Fentanyl Citrate Injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor, could result in lower than expected fentanyl plasma concentrations and, decrease efficacy. When using Fentanyl Citrate Injection with CYP3A4 inducers, or discontinuation of a CYP3A4 inhibitor, monitor patients closely at frequent intervals and consider increasing the Fentanyl Citrate Injection dosage [see Dosage and Administration (2.1), Drug Interactions (7)].