Each mL contains 50 mcg fentanyl (as fentanyl citrate).
Excipients/Inactive Ingredients: The inactive ingredients of the injectable solution are sodium chloride and water for injection.
Pharmacology: Pharmacodynamics: Mechanism of action: Fentanyl is a potent, opioid analgesic.
Pharmacodynamic effects: Fentanyl is an opioid analgesic interacting predominantly with the μ-opioid receptor. Fentanyl can be used as an analgesic supplement to general anesthesia or as the sole anesthetic. Fentanyl preserves cardiac stability and obtunds stress-related hormonal changes at higher doses. A dose of 100 mcg (2.0 mL) is approximately equivalent in analgesic activity to 10 mg of morphine. The onset of action is rapid. However, the maximum analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is approximately 30 minutes after a single IV dose of up to 100 mcg. Depth of analgesia is dose-related and can be adjusted to the pain level of the surgical procedure.
Like other opioid analgesics, Fentanyl citrate (Sublimaze), depending upon the dose and speed of administration, can cause muscle rigidity, as well as euphoria, miosis and bradycardia.
Histamine assays and skin-wheal testing have indicated that clinically significant histamine release is rare with Fentanyl citrate (Sublimaze).
All actions of Fentanyl citrate (Sublimaze) are reversed by a specific opioid antagonist.
Pharmacokinetics: Distribution: After intravenous injection, Fentanyl plasma concentrations fall rapidly, with sequential distribution half-lives of about 1 minute and 18 minutes and a terminal elimination half-life of 475 minutes. Fentanyl has a Vc (volume of distribution of the central compartment) of 13 L, and a total Vdss (distribution volume at steady-state) of 339 L. The plasma-protein binding of Fentanyl is about 84%.
Metabolism: Fentanyl is rapidly metabolized, mainly in the liver by CYP3A4. The major metabolite is norfentanyl. Fentanyl clearance is 574 mL/min.
Excretion: Approximately 75% of the administered dose is excreted in the urine within 24 hours and only 10% of the dose eliminated in urine is present as unchanged drug.
Special Populations: Pediatrics: The plasma protein binding of fentanyl in newborns is approximately 62% which is lower than in adults. The clearance and the volume of distribution are higher in infants and children. This may result in an increased dose requirement for Fentanyl citrate (Sublimaze).
Renal impairment: Data obtained from a study administering IV fentanyl in patient undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population. If patients with renal impairment receive Fentanyl citrate (Sublimaze), they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Dosage & Administration).
Adult patients with burns: An increase in clearance up to 44% together with a larger volume of distribution results in lower fentanyl plasma concentrations. This may require an increased dose of Fentanyl citrate (Sublimaze).
Obese Patients: An increase in clearance of fentanyl is observed with increased body weight. In patients with a BMI > 30, clearance of fentanyl increases by approximately 10% per 10 kg increase of the fat free mass (lean body mass).
Toxicology: Non-Clinical Information: Fentanyl has a broad safety margin. In rats the ratio LD50/ED50 for the lowest level of analgesia is 281.8, as compared with 69.5 and 4.8 for morphine and pethidine respectively.
Carcinogenicity and Mutagenicity: In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation. Fentanyl showed no evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays. In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 mcg/kg/day in males or 100 mcg/kg/day in females, which were the maximum tolerated doses for males and females.
Reproductive Toxicology: Fertility: Some tests on female rats showed reduced fertility as well as embryo mortality. These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo.
There was no evidence of teratogenic effects.
Fentanyl citrate (Sublimaze) is indicated: for use as an opioid analgesic supplement in general or regional anesthesia; for 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; for use as an anesthetic agent with oxygen in selected high-risk patients undergoing major surgery.
The dosage of Fentanyl citrate (Sublimaze) should be individualized according to age, body weight, physical status, underlying pathological condition, use of other drugs, and type of surgery and anesthesia.
Use as an analgesic supplement to general anesthesia: Analgesia during anesthetic induction: 1-10 mcg/kg: Fentanyl citrate (Sublimaze) in small doses is most useful for minor surgery.
Analgesic during maintenance of anesthesia: For both balanced anesthesia and total intravenous anesthesia (TIVA), dose amounts and the intervals between doses should be adjusted to account for the duration and severity of the surgical procedure.
Bolus administration: 0.5-10 mcg/kg.
Continuous infusion: 0.5-5 mcg/kg/h.
Use as an anesthetic agent: When attenuation of the response to surgical stress is especially important, doses of 50-100 mcg/kg may be administered with oxygen and a muscle relaxant. This technique provides anesthesia without necessitating the use of additional anesthetic agents. In certain cases, doses up to 150 mcg/kg may be required to produce this anesthetic effect. Fentanyl citrate (Sublimaze) has been used in this fashion 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.
Special populations: Pediatrics: For induction and maintenance in children aged 2-12 years, a dose of 2-3 mcg/kg is recommended.
Elderly and debilitated patients: As with other opioids, the initial dose should be reduced in the elderly (>65 years of age) and in debilitated patients. The effect of the initial dose should be taken into account in determining supplemental doses.
Obese patients: In obese patients there is a risk of overdosing if the dose is calculated based on body weight. Obese patients should be dosed based on estimated lean body mass rather than on body weight only.
Renal impairment: In patients with renal impairment reduced dosing of Fentanyl citrate (Sublimaze) should be considered and these patients should be observed carefully for signs of fentanyl toxicity (see Pharmacology: Pharmacokinetics under Actions).
Symptoms and signs: An overdosage of Fentanyl citrate (Sublimaze) manifests itself as an extension of its pharmacologic actions. Respiratory depression which can vary in severity from bradypnea to apnea may occur.
Treatment: In the presence of hypoventilation or apnea, oxygen should be administered and respiration should be assisted or controlled as indicated. A specific opioid antagonist should be used as indicated to control respiratory depression. This does not preclude the use of more immediate countermeasures. The respiratory depression may last longer than the effect of the antagonist; additional doses of the latter may therefore be required.
If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assisted or controlled respiration.
The patient should be carefully observed; body warmth and adequate fluid intake should be maintained. If hypotension is severe or if it persists, the possibility of hypovolemia should be considered, and if present, should be controlled with appropriate parenteral fluid administration.
Known intolerance to any of its components or to other opioids.
Respiratory depression: As with all potent opioids, respiratory depression is dose related and can be reversed by a specific opioid antagonist, but additional doses may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist. Profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the postoperative period. Therefore, patients should remain under appropriate surveillance. Resuscitation equipment and narcotic antagonists should be readily available. Hyperventilation during anesthesia may alter the patient's responses to CO2, thus affecting respiration postoperatively.
Muscle rigidity: Induction of muscle rigidity, which may also involve the thoracic muscles, can occur, but can be avoided by the following measures: slow IV injection (ordinarily sufficient for lower doses), premedication with benzodiazepines and the use of muscle relaxants. Non-epileptic (myo)clonic movements can occur.
Cardiac disease: Bradycardia, and possibly cardiac arrest, can occur if the patient has received an insufficient amount of anticholinergic, or when Fentanyl citrate (Sublimaze) is combined with non-vagolytic muscle relaxants. Bradycardia can be treated with atropine.
Opioids may induce hypotension, especially in hypovolemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.
Special dosing conditions: The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients the transient decrease in the mean arterial pressure has occasionally been accompanied by a short-lasting reduction of the cerebral perfusion pressure.
Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.
It is recommended to reduce the dosage in the elderly and in debilitated patients. Opioids should be titrated with caution in patients with any of the following conditions: uncontrolled hypothyroidism; pulmonary disease; decreased respiratory reserve; alcoholism; or impaired hepatic or renal function. Such patients also require prolonged post-operative monitoring.
Interaction with neuroleptics: If Fentanyl citrate (Sublimaze) is administered with a neuroleptic, the user should be familiar with the special properties of each drug, particularly the difference in duration of action. When such a combination is used, there is a higher incidence of hypotension. Neuroleptics can induce extrapyramidal symptoms that can be controlled with anti-Parkinson agents.
Serotonin syndrome: Caution is advised when Fentanyl citrate (Sublimaze) is co-administered with drugs that affect the serotonergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.
Serotonin syndrome may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea).
If serotonin syndrome is suspected, rapid discontinuation of Fentanyl citrate (Sublimaze) should be considered.
Effects on Ability to Drive and Use Machines: Patients should only drive or operate a machine if sufficient time has elapsed (at least 24 hours) after the administration of Fentanyl citrate (Sublimaze).
Pregnancy: There are no adequate data from the use of Fentanyl citrate (Sublimaze) in pregnant women. Fentanyl citrate (Sublimaze) can cross the placenta in early pregnancy. Studies in animals have shown some reproductive toxicity (see Pharmacology: Toxicology: Non- Clinical Information under Actions). The potential risk for humans is unknown.
Administration (intramuscular (IM) or IV) during childbirth (including cesarean section) is not recommended because fentanyl crosses the placenta and may suppress spontaneous respiration in the newborn period. If Fentanyl citrate (Sublimaze) is administered, assisted ventilation equipment must be immediately available for the mother and infant if required. An opioid antagonist for the child must always be available.
Breast-feeding: Fentanyl is excreted into human milk. Therefore, breast-feeding is not recommended for 24 hours following the administration of this drug. The risk/benefit of breastfeeding following Fentanyl citrate (Sublimaze) administration should be considered.
Fertility: There are no clinical data on the effects of fentanyl on male or female fertility. In animal studies, some tests on rats showed reduced female fertility at maternal toxic doses (see Pharmacology: Toxicology: Non-Clinical Information under Actions).
Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of fentanyl citrate based on the comprehensive assessment of the available adverse event information. A causal relationship with fentanyl citrate cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trial Data:
The safety of Fentanyl citrate (Sublimaze) was evaluated in 376 subjects who participated in 20 clinical trials evaluating Fentanyl citrate (Sublimaze) used as an anesthetic. These subjects took at least one dose of Fentanyl citrate (Sublimaze) and provided safety data. Adverse reactions, as identified by the investigator, reported for ≥1% of Fentanyl citrate (Sublimaze)-treated subjects in these studies are shown in Table 1. (See Table 1.)
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Additional adverse reactions that occurred in <1% of Fentanyl citrate (Sublimaze)-treated subjects in the 20 clinical trials are listed as follows in Table 2. (See Table 2.)
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Adverse reactions first identified during postmarketing experience with Fentanyl citrate (Sublimaze) are included in Table 3. In the table, the frequencies are provided according to the following convention: Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥1/1,000 and < 1/100; Rare ≥ 1/10,000 and < 1/1,000; Very rare < 1/10,000, including isolated reports.
In Table 3, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 3.)
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When a neuroleptic is used with Fentanyl citrate (Sublimaze), the following adverse reactions may be observed: chills and/or shivering; restlessness, postoperative hallucinatory episodes; and extrapyramidal symptoms (see Precautions).
Effect of Other Drugs on Fentanyl citrate (Sublimaze): Central Nervous System (CNS) depressants: Drugs such as barbiturates, benzodiazepines, neuroleptics, general anesthetics, and other, non-selective CNS depressants (e.g. alcohol) may potentiate the respiratory depression of opioids. When patients have received such drugs, the dose of Fentanyl citrate (Sublimaze) required may be less than usual. Concomitant use with Fentanyl citrate (Sublimaze) in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death.
Cytochrome P450 3A4 (CYP3A4) inhibitors: Fentanyl, a high clearance drug, is rapidly and extensively metabolized mainly by CYP3A4. When Fentanyl citrate (Sublimaze) is used, the concomitant use of a CYP3A4 inhibitor may result in a decrease in fentanyl clearance. With single-dose Fentanyl citrate (Sublimaze) administration, the period of risk for respiratory depression may be prolonged, which may require special patient care and longer observation. With multiple-dose Fentanyl citrate (Sublimaze) administration, the risk for acute and/or delayed respiratory depression may be increased, and a dose reduction of Fentanyl citrate (Sublimaze) may be required to avoid accumulation of fentanyl. Oral ritonavir (a potent CYP3A4 inhibitor) reduced the clearance of a single intravenous Fentanyl citrate (Sublimaze) dose by two thirds, although peak plasma concentrations of fentanyl were not affected. However, itraconazole (another potent CYP3A4 inhibitor) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of a single intravenous Fentanyl citrate (Sublimaze) dose. Co-administration of other potent or less potent CYP3A4 inhibitors, such as voriconazole or fluconazole, and Fentanyl citrate (Sublimaze) may also result in an increased and/or prolonged exposure to fentanyl.
Monoamine Oxidase Inhibitors (MAOI): It is usually recommended to discontinue MAOIs 2 weeks prior to any surgical or anesthetic procedure. However, several reports describe the uneventful use of Fentanyl citrate (Sublimaze) during surgical or anesthetic procedures in patients on MAOIs.
Serotonergic Drugs: Co-administration of fentanyl with a serotonergic agent, such as a SSRI, SNRI or MAOI, may increase the risk of serotonin syndrome, a potentially life-threatening condition.
Effect of Fentanyl citrate (Sublimaze) on Other Drugs: Following the administration of Fentanyl citrate (Sublimaze), the dose of other CNS-depressant drugs should be reduced. This is particularly important after surgery, because profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the postoperative period. Administration of a CNS depressant, such as a benzodiazepine, during this period may disproportionally increase the risk for respiratory depression.
The total plasma clearance and volume of distribution of etomidate is decreased by a factor 2 to 3 without a change in half-life when administered with fentanyl. Simultaneous administration of Fentanyl citrate (Sublimaze) and intravenous midazolam results in an increase in the terminal plasma half-life and a reduction in the plasma clearance of midazolam. When these drugs are co-administered with Fentanyl citrate (Sublimaze), their dose may need to be reduced.
Instructions for Use and Handling: Wear gloves while opening ampule.
Maintain the ampule between the thumb and index finger, leaving the tip of the ampule free.
With the other hand, hold the tip of ampule, putting the index finger against the neck of the ampule and the thumb on the colored point, in parallel to the identification colored ring(s).
Keeping the thumb on the point, sharply break the tip of the ampule while firmly holding the other part of the ampule in the hand.
Accidental dermal exposure should be treated by rinsing the affected area with water. Avoid usage of soap, alcohol, and other cleaning materials that may cause chemical or physical abrasions to the skin.
Incompatibilities: The injectable solution must not be mixed with other products.
If desired, Fentanyl citrate (Sublimaze) may be mixed with sodium chloride or glucose intravenous infusions. Such dilutions are compatible with plastic infusion sets. These should be used within 24 hours of preparation.
Protect from light.
Store at temperatures not exceeding 25°C.
N01AH01 - fentanyl ; Belongs to the class of opioid anesthetics. Used as general anesthetics.
Soln for inj (amp) 50 mcg/mL x 2 mL x 5's, 10 mL x 5's.