Fentanyl Injection is a clear, colorless solution for injection containing fentanyl citrate equivalent to fentanyl 50 microgram per mL.
Fentanyl citrate is a white or almost white powder, soluble in water, freely soluble in methanol, sparingly soluble in alcohol.
The chemical formula of fentanyl citrate is C22H28N2O.C6H8O7 and its molecular weight is 528.6.
Fentanyl Injection is a sterile solution of fentanyl citrate and sodium chloride in Water for Injections. It is presented in ampoules and containing 2 mL or 10 mL of a 50 microgram per mL solution of fentanyl present as fentanyl citrate. The solution does not contain any preservative. The pH of the solution is adjusted with sodium hydroxide or hydrochloric acid to 5.0 to 7.5, if necessary.
Excipients/Inactive Ingredients: Hydrochloric acid, Sodium chloride, Sodium hydroxide, Water for injections.
Pharmacology: Pharmacodynamics: Mechanism of action: Fentanyl is a synthetic opioid analgesic related to the phenylpiperidines such as morphine. As an analgesic it is estimated to be about 80 times more potent than morphine. As with morphine and pethidine in equianalgesic doses, fentanyl produces respiratory depression but there is a quicker return to normal respiration in healthy individuals.
Fentanyl citrate unlike other phenylpiperidines rarely produces histamine release and exhibits little hypnotic activity.
Clinical trials: No data available.
Pharmacokinetics: Absorption: Following parenteral administration via intravenous or intramuscular injection the action of fentanyl is rapid. Peak analgesic effect occurs within several minutes and has a duration of 30 to 60 minutes following a single dose of up to 100 micrograms given intravenously. Respiratory depressant effects last longer than analgesia.
Distribution: After intravenous injection, serum concentrations of fentanyl have been shown to decrease rapidly to about 20% of peak concentrations within 5 minutes of injection, followed by a slower decrease over the next 10 to 20 minutes to stabilize at a low concentration for 2 hours after injection. The short duration of action is probably due to the redistribution with up to 70% being bound to plasma proteins.
Metabolism: Fentanyl citrate is metabolized, mainly in the liver, to inactive metabolites norfentanyl, 4-N-anilinopiperidine and propionic acid.
Excretion: About 20% of the drug is excreted in the urine within 8 hours with up to 90% as the metabolites and 10% as unchanged fentanyl.
Toxicology: Preclinical Safety Data: Genotoxicity: No data available.
Carcinogenicity: No data available.
Fentanyl Citrate is indicated for analgesic action of short duration during premedication, induction and maintenance of anesthesia and in the immediate post-operative periods. It may be used as an opioid analgesic supplement in general and regional anesthesia.
Fentanyl may be used in combination with neuroleptic agents such as droperidol as an anesthetic premedication, for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. The state of neurolept analgesia may be converted to neurolept anesthesia by the concurrent administration of 65% nitrous oxide in oxygen.
Dosage: Adult Dosage: Premedication: 50 to 100 micrograms (1 to 2 mL) fentanyl administered intramuscularly 30 to 60 minutes prior to surgery (modified for high risk patients).
Adjunct to general anesthesia induction: 50 to 100 micrograms (1 to 2 mL) administered intravenously and repeated at 2 to 3 minute intervals, until the desired effect is achieved (25 to 50 micrograms is recommended for high-risk patients). 25 to 50 micrograms (0.5 to 1 mL) should be administered intravenously or intramuscularly when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia.
Adjunct to regional anesthesia: 50 to 100 micrograms administered intramuscularly or by slow intravenous injection.
Postoperatively: 50 to 100 micrograms administered intramuscularly repeated in 1 to 2 hours as needed.
Children's dosage: Do not use Fentanyl Citrate in children less than 2 years of age. For children aged between 2 to 12 years, fentanyl may be used for induction and maintenance at a reduced level as low as 20 to 30 micrograms per 10 kg bodyweight.
Use in elderly patients: Elderly patients may require lower doses of fentanyl and a varied dosage regimen as they may be more susceptible to adverse effects, such as respiratory depression and cardiovascular effects.
Method of Administration: Fentanyl citrate is administered by intramuscular or intravenous injection only.
The dosage of fentanyl should be given in the smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence. Dosage should be individualized to take into account physical condition and reactions with other drugs.
Reduced dosage is generally indicated for high-risk patients, including geriatric or debilitated patients, or those who have received other CNS depressant drugs. When used in conjunction with other CNS depressants as low as 25 to 33% of the usual dose is recommended.
Contains no antimicrobial agent. Product is for single use in one patient only. Discard any residue.
Dosage Adjustments: Renal impairment: Fentanyl should be used with caution in patients with impaired renal function.
Hepatic impairment: Fentanyl should be used with caution in patients with impaired hepatic function.
The manifestations of fentanyl overdose are an extension of its pharmacological actions.
Respiration may need to be assisted or controlled and an adequate airway be maintained. An opioid antagonist such as naloxone should be available to manage respiratory depression. However, it should be remembered that the duration of respiratory depression may be longer than the duration of action of the opioid antagonist and other more immediate and supportive treatment should be initiated.
If respiratory depression is associated with muscle rigidity, it may be necessary to facilitate assisted or controlled respiration with the use of a neuromuscular blocking agent. If hypotension occurs and is possibly associated with hypovolemia, appropriate fluid therapy should be used.
Bradycardia may be treated by administering atropine or a neuromuscular blocking agent with vagolytic activity such as pancuronium or gallamine.
Hypotension may be treated by administration of appropriate parenteral fluid therapy. Repositioning of the patient to improve venous return to the heart should be considered and if necessary, a vasopressor and/or naloxone (postoperatively only) may be administered.
Other supportive measures should also be employed as needed.
Fentanyl is contraindicated in patients with a known hypersensitivity or intolerance to fentanyl or other opioid analgesics.
It should not be administered to patients who fall into the following categories: Children less than 2 years old, because the safety of fentanyl in this age group has not been established.
Patients suffering from bronchial asthma.
Patients who may be particularly susceptible to respiratory depression such as comatose patients who may have head injury, brain tumor or increased intracranial pressure.
Patients who have received monoamine oxidase (MAO) inhibitors within the previous 14 days (see Interactions).
Patients with myasthenia gravis: Fentanyl may cause thoracic muscle rigidity following intravenous administration. It should not be used in patients with a history of myasthenia gravis, as reversal of thoracic muscle rigidity with muscle relaxants is inappropriate in these patients.
As with other opioid analgesics, fentanyl can produce drug dependence with the potential to be habit forming.
Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.
Intravenous administration of fentanyl may cause muscle rigidity, particularly of the muscles of respiration and alter the rate of respiration especially in patients suffering from myasthenia gravis. The effect appears to be dependent on the rate of injection. The incidence may be lowered by giving the intravenous injection more slowly. Muscle relaxants may be necessary.
Non-epileptic myoclonic movements can occur.
Patients receiving fentanyl should be kept under close medical supervision. Resuscitative facilities and an opioid antagonist compatible with the patient's condition should be available for the management of complications.
Certain forms of conduction anesthesia, such as spinal anesthesia and some peridural anesthetics can alter respiration by blocking intercostal nerves. Through other mechanisms fentanyl can also alter respiration. Therefore, when fentanyl 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 patients selected for these forms of anesthesia.
Profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the post-operative period. Hyperventilation during anesthesia may alter the patient's responses to CO2, thus affecting respiration post-operatively. Therefore patients should remain under appropriate surveillance.
It has been reported that diminished sensitivity to CO2 stimulation may persist longer than depression of respiratory rate. This dose related effect of respiratory depression peaks between 5 and 15 minutes after injection, but seldom lasts longer than 30 minutes.
The effect on respiratory depression persists longer than the measured analgesic effect, and care should be taken, with the total opioid dose taken into account when fentanyl is given postoperatively. The recommended dose may be as low as quarter of that normally prescribed.
When fentanyl is used in conjunction with neuroleptics such as droperidol, the differing duration of action should be taken into account. Hypotension can occur which may be due to hypovolemia so appropriate parenteral therapy should be readily available.
Fentanyl should only be used by experienced physicians and in patients who are under constant supervision.
Fentanyl should be administered with caution to patients with severe impairment of pulmonary function (e.g., chronic obstructive pulmonary disease, patients with decreased respiratory reserve or any patient with potentially compromised respiration), due to the possibility o f respiratory depression. In such patients, opioids may further decrease respiratory drive and increase airway resistance. During anesthesia this may be managed by assisted or controlled respiration.
Dosage reduction is desirable in patients suffering from hypothyroidism, chronic hepatic disease and alcoholism.
Fentanyl should be used with caution in patients with cardiac arrhythmias (due to its weak cholinergic activity). Fentanyl may produce bradycardia, and possibly asystole, if the patient has received an insufficient amount of anticholinergic agent, or when fentanyl is combined with non-vagolytic muscle relaxants.
Opioids may induce hypotension, particularly in hypovolemic patients. Appropriate measures should be taken to maintain stable arterial pressure.
Caution is advised when fentanyl 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), 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 should be considered.
Effects on laboratory tests: No data available.
Effects on Ability to Drive and Use Machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in hepatic impairment: Fentanyl should be administered with caution to patients with liver dysfunction.
Use in renal impairment: Fentanyl should be administered with caution to patients with kidney dysfunction.
Use in Children: Safe use of fentanyl in children younger than 2 years has not been established. It should not be administered in children younger than 2 years of age.
Use in Elderly: Elderly patients may require lower doses of fentanyl and a varied dosage regimen as they may be more susceptible to adverse effects, such as respiratory depression and cardiovascular effects. They may also have age-related kidney function impairment, resulting in lower clearance rates of fentanyl.
Effects on fertility: No data available.
Use in pregnancy-Category C: Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible.
Although no teratogenic or acute embryotoxic effects have been observed in animal experiments, insufficient data are available to evaluate any harmful effects in man. Consequently, the risks and potential benefits should be considered before this drug is administered to pregnant patients.
Opioid analgesics may cause respiratory depression in the newborn infant. Administration during childbirth (including cesarean section) is not recommended, because fentanyl crosses the placenta and because the fetal respiratory center is particularly sensitive to opioids. If fentanyl is administered during childbirth, an antidote should be available for the baby.
Use in lactation: Fentanyl may enter breast milk. Therefore, breast-feeding is not recommended for 24 hours following administration of fentanyl.
The major adverse reactions associated with fentanyl are respiratory depression, apnea, muscle rigidity, myoclonic movements and bradycardia, which if untreated, can lead to conditions such as cardiac arrest, circulatory depression and respiratory arrest.
Respiratory depression (usually associated with intravenous use) can be immediately reversed by an opioid antagonist. The respiratory depression is more likely to occur if the intravenous injection is given too rapidly; it rarely occurs with intramuscular injection. Secondary rebound respiratory depression has been observed after the operation in rare instances.
Muscle rigidity is a common side effect, and may be associated with reduced pulmonary compliance and/or apnea, laryngospasm or bronchospasm. It may be reversed by intravenous administration of a muscle relaxant such as suxamethonium followed by controlled or artificial respiration.
Bradycardia can be controlled by the use of atropine. Bradycardia and other cholinergic effects are less likely if atropine or other anticholinergic agents are included in the pre-anesthetic regimen.
Other reported adverse effects of fentanyl, when used alone, include elevated blood pressure, hypotension, blurred vision, dizziness, nausea, emesis, laryngospasm, diaphoresis, itching, euphoria and spasm of the sphincter of Oddi.
Less frequently, cardiac arrhythmias, postoperative mental depression, paradoxical CNS excitation or delirium may occur. Motor stimulation and bronchospasm may occur with high doses of fentanyl. Miosis or seizures may occur.
When used in conjunction with a neuroleptic agent such as droperidol, reported adverse effects include chills and/or shivering, restlessness, post operative hallucinations, drowsiness, mental depression and extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis). These have been observed up to 24 hours postoperatively. Elevated blood pressure, with or without pre-existing hypertension, has been reported following administration of fentanyl combined with droperidol. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anesthetic and surgical stimulation during light anesthesia.
Allergic reactions (such as anaphylaxis, bronchospasm, pruritis, urticaria) and asystole have been reported following the co-administration of several drugs during anesthesia. However, it is uncertain whether these reactions have a causal relationship with fentanyl.
CNS Depressants: Other drugs with CNS depressant activity, e.g., barbiturates, general anesthetics, tranquilizers, other opioids, benzodiazepines, neuroleptics and alcohol; fentanyl may have additive or potentiating effects with these drugs.
Patients who have received other CNS depressant drugs will require a lower dose of fentanyl than usual. Likewise, following the administration of fentanyl, the dose of other CNS depressant drugs should also be reduced. Post-operative opioids, including fentanyl and other CNS depressant drugs should be given initially in reduced doses, as low as ¼ to ⅓ of doses usually recommended. The total dose of all opioid analgesics should be taken into account before giving opioid analgesics during recovery from anesthesia.
MAO Inhibitors: Untoward incidents resulting from concurrent administration of opioids and MAO inhibitors have occurred. Nearly all of these reports have involved pethidine, but the safety of fentanyl has not been established in this situation. Therefore, before receiving fentanyl, patients should not have taken a MAO inhibitor within the previous 14 days.
Serotonergic Drugs: Co-administration of fentanyl with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI), a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition.
Neuroleptics: The combination of fentanyl with a neuroleptic such as droperidol may cause hypotension (see Precautions). If this occurs, the possibility of hypovolemia should also be considered. Care should be exercised in moving and positioning patients because of the possibility of orthostatic hypotension. If fluid therapy, together with other countermeasures, do not correct hypotension it may be necessary to administer a pressor agent other than adrenaline. Adrenaline may paradoxically decrease blood pressure in patients who have received droperidol due to its alpha-adrenergic blocking action. The EEG pattern may return to normal only slowly when droperidol is used with fentanyl. This should be taken into account if the EEG pattern is used for postoperative monitoring.
Nitrous oxide: Nitrous oxide has been reported to produce cardiovascular depression when given with high doses of fentanyl.
Amiodarone: Profound bradycardia, sinus arrest and hypotension have occurred when patients receiving amiodarone have been given fentanyl for anesthesia.
Incompatibilities: Fentanyl is incompatible with thiopentone sodium and methohexitone sodium.
Store at temperatures not exceeding 25°C.
N01AH01 - fentanyl ; Belongs to the class of opioid anesthetics. Used as general anesthetics.
Inj (amp) (clear, colorless) 500 mcg/10 mL x 5's. 1000 mcg/20 mL x 5's.