1. Name Of The Medicinal Product
Fentanyl Injection 50 micrograms/ml.
2. Qualitative And Quantitative Composition
Contains Fentanyl citrate the equivalent of 50 micrograms of Fentanyl in 1ml.
Each 2ml ampoule contains 100 micrograms of Fentanyl as Fentanyl citrate.
Each 10ml ampoule contains 500 micrograms of Fentanyl as Fentanyl citrate.
3. Pharmaceutical Form
Solution for injection.
A clear, colourless, sterile solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Fentanyl citrate is a narcotic analgesic. In low doses it is used to provide analgesia during short surgical procedures and as a premedicant. In higher doses it is employed as an analgesic/respiratory depressant in patients who need assisted ventilation. In combination with a neuroleptic drug, fentanyl is employed as part of the technique of neuroleptanalgesia. Fentanyl citrate is also used in the treatment of severe pain, such as that of myocardial infarction.
4.2 Posology And Method Of Administration
Routes of administration:
Fentanyl should be given only in an environment where the airway can be controlled and by personnel who can control the airway (see section 4.4).
Intravenous and Intramuscular routes. Fentanyl Injection can be administered to both adults and children via the intravenous route as a bolus or as an infusion. The dose should be individualised according to age, body weight, physical status, any underlying pathological condition, concomitant medication, and type of surgery and anaesthesia. The usual dosage regimen is as follows:
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Doses greater than 200 micrograms are solely for use in anaesthesia.
As a premedicant, 1 - 2ml may be administered intramuscularly before induction of anaesthesia.
Following intravenous administration in the non-premedicated adult patient, 2ml fentanyl may be anticipated to provide adequate analgesia for 10 – 20 minutes in surgical procedures involving low pain intensity. A bolus of 10ml of fentanyl can be expected to provide analgesia for about one hour. The analgesia produced is generally adequate for surgery involving moderate pain intensity. Administration of 50 microgram/kg will provide intense analgesia for some four to six hours for surgery associated with intense stimulation.
Fentanyl Injection may also be administered as an intravenous infusion.
Ventilated patients may be given a loading dose as a fast infusion of approximately 1 microgram/kg/minute for the first 10 minutes, followed by an infusion of approximately 0.1 microgram/kg/minute. Alternatively, the loading dose may be administered as a bolus. The rate of infusion should be titrated to the individual patient response and lower infusion rates may be adequate. The infusion should be discontinued approximately 40 minutes before the end of surgery, unless post-operative ventilation is intended.
Lower infusion rates, e.g. 0.05 - 0.08 microgram/kg/minute, are required if spontaneous ventilation is to be maintained. Higher infusion rates of up to 3 micrograms/kg/minute have been employed in cardiac surgery.
It is important when estimating the required dose to assess the likely degree of surgical stimulation, the effect of premedicant drugs, and the duration of the procedure.
Use in elderly and debilitated patients: It is important to reduce the dosage in the elderly and in debilitated patients. The effect of the initial dose of fentanyl should be considered when determining supplemental dosage.
Paediatric population
Children aged 12 to 17 years old- Follow adult dosage:
Children aged 2 to 11 years old:
The usual dosage regimen in children is as follows:
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Use in children:
Analgesia during operation, enhancement of anaesthesia with spontaneous respiration
Techniques that involve analgesia in a spontaneous breathing child should only be used as part of an anaesthetic technique, or given as part of a sedation/ analgesia technique with experienced personnel in an environment that can manage sudden chest wall rigidity requiring intubation, or apnoea requiring airway support.
4.3 Contraindications
Known hypersensitivity to fentanyl citrate: respiratory depression: obstructive airways disease. Concurrent administration with monoamine oxidase inhibitors or within two weeks of their discontinuation. Known intolerance to fentanyl or other morphinomimetics.
In patients after operative interventions in the biliary tract.
4.4 Special Warnings And Precautions For Use
Warnings:
Repeated use of fentanyl may result in the development of tolerance and dependence.
Intravenous administration of fentanyl may result in a transient fall in blood pressure, particularly in patients with hypovolaemia, and appropriate measures should be taken to maintain a stable arterial pressure.
Significant respiratory depression will occur if doses of fentanyl in excess of 200 micrograms are administered. This effect and the other pharmacological effects of fentanyl can be reversed by specific narcotic antagonists, such as naloxone. Since the duration of respiratory depression may outlast the duration of action of the narcotic antagonist, additional doses of the antagonist may be required.
Bradycardia and possibly asystole may occur in non-atropinised patients and can be antagonised by atropine.
Muscle rigidity, including rigidity of the thoracic muscles, may occur and may be avoided by adopting the following measures: giving intravenous injection slowly (which is usually sufficient for lower doses), premedicating with a benzodiazepine, administration of a muscle relaxant.
Precautions:
Fentanyl should be given only in an environment where the airway can be controlled and by personnel who can control the airway.
As with all narcotic analgesics, care should be observed when administering fentanyl to patients with myasthenia gravis.
It is desirable to reduce dosage in the elderly and in debilitated patients.
Careful dosage titration is required in hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and impaired renal or hepatic function, and prolonged monitoring may be required.
Patients on prolonged opioid therapy or with a history of opioid abuse may require higher doses of fentanyl.
Administration of fentanyl during labour may result in neonatal respiratory depression.
As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early postoperative period. It is imperative to ensure that adequate spontaneous breathing has been established and maintained before discharge from the recovery area whenever large doses or infusions of Fentanyl Citrate Injection have been administered.
Hyperventilation during anaesthesia may alter the patient's response to CO2, thus affecting respiration post-operatively.
Opioid pre-medication may potentiate or prolong respiratory depressant effects of fentanyl citrate. Resuscitation facilities and opioid antagonists should be readily available.
Rapid bolus injection of opioids should be avoided in patients with compromised cerebrovascular compliance, as the transient decrease in mean arterial pressure has occasionally been accompanied by a transient reduction of the cerebral perfusion pressure in such patients.
Paediatric population:
Techniques that involve analgesia in a spontaneous breathing child should only be used as part of an anaesthetic technique, or given as part of a sedation/ analgesia technique with experienced personnel in an environment that can manage sudden chest wall rigidity requiring intubation, or apnoea requiring airway support.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Effect of other drugs on fentanyl
The respiratory depressant effect of fentanyl may be enhanced or prolonged by opioid premedication, barbiturates, benzodiazepines, neuroleptics, halogenic gasses, alcohol and other non-selective CNS depressants.
In patients who have received a CNS depressant, the dose of fentanyl will be less than usual.
When fentanyl is used in combination with non-vagolytic muscle relaxants, bardycardia and possibly asystole may occur.
Concomitant use of fentanyl and droperidol can result in higher incidence of hypotension.
Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4. Itraconazole ( a potent CYP3A4 inhibitor ) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of iv fentanyl.
Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of iv fentanyl by two thirds; however, peak plasma concentrations after a single dose of fentanyl were not affected.
When fentanyl is used in a single dose, the concomitant use of potent CYP3A4 inhibitors such as ritonavir requires special patient care and observation.
Co-administration of fluconazole or voriconazole (moderate CYP3A4 inhibitors) and fentanyl may result in an increased exposure to fentanyl.
With continuous treatment of fentanyl and concomitant administration of CYP3A4 inhibitors, dose reduction of fentanyl may be required to avoid accumulation of fentanyl, which may increase the risk of prolonged or delayed respiratory depression.
Pretreatment with, or concurrent administration of, cimetidine may increase plasma levels of fentanyl, when repeated doses of both drugs are used.
Bradycardia may be intensified by pretreatment with, or concurrent use of, drugs such as beta-blockers, suxamethonium, halothane, vecuronium, which may themselves cause bradycardia.
Effect of fentanyl on other drugs
Following the administration of fentanyl, the dose of other CNS depressant drugs should be reduced.
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 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 their dose may need to be reduced.
4.6 Pregnancy And Lactation
There are no adequate data from the use of fentanyl in pregnant women. Fentanyl can cross the placenta in early pregnancy. Studies in animals have shown some reproductive toxicity. The potential risk for humans is unknown.
Fentanyl crosses the placenta and administration during childbirth, including caesarean section, is not recommended because of the risk of respiratory depression in the new-born infant. If fentanyl is administered during childbirth, a narcotic antagonist should be available for use in the neonate.
Fentanyl is excreted into human milk. It is therefore recommended that breast-feeding is not initiated within 24 hours of treatment. The risk/benefit of breast-feeding following fentanyl administration should be considered.
4.7 Effects On Ability To Drive And Use Machines
Where early discharge is envisaged, patients should be advised not to drive or to operate machinery for 24 hours following administration of fentanyl.
4.8 Undesirable Effects
The following table displays ADRs that have been reported with the use of fentanyl IV from either clinical trials or postmarketing experiences. The displayed frequency categories use the following convention: Very common (
Table 1: Adverse Drug Reactions
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When a neuroleptic is used with fentanyl, the following adverse reactions may be observed: chills and/or shivering, restlessness, postoperative hallucinatory episodes and extrapyramidal symptoms (see Section 4.4).
4.9 Overdose
Symptoms
An overdose of fentanyl manifests itself as an extension of its pharmacologic actions. Depending on the individual sensitivity, the clinical picture is determined primarily by the degree of respiratory depression, which varies from bradypnoea to apnoea.
Treatment
In the presence of hypoventilation or apnoea, oxygen should be administered and respiration should be assisted or controlled as indicated. A specific opioid antagonist, such as naloxone, 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 hypovolaemia should be considered and, if present, it should be controlled with appropriate parenteral fluid administration.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Fentanyl is a well established chemical entity. It is an opioid analgesic with a high affinity for the μ-opioid receptor. Belonging to the ATC code group of N01AH01.
Fentanyl can be used as an analgesic supplement to general anaesthesia or as the sole anaesthetic. Fentanyl preserves cardiac stability, and obtunds stress-related hormonal changes at higher doses. A dose of 100 micrograms (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 micrograms. Depth of analgesia is dose-related and can be adjusted to the pain level of the surgical procedure. Fentanyl has a broad safety margin. In rats, the ratio LD50/ED50 for the lowest level of analgesia is 277, as compared with 69.5 and 4.6 for morphine and pethidine respectively.
Like other opioid analgesics, fentanyl, 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 in man, as well as in vivo testing in dogs, have indicated that clinically significant histamine release is rare with fentanyl.
All actions of fentanyl are immediately and completely reversed by a specific opioid antagonist, such as naloxone.
5.2 Pharmacokinetic Properties
Fentanyl is a lipid-soluble drug and its pharmacokinetics can be described in terms of a three-compartment model. Following intravenous injection, there is a short distribution phase during which high concentrations of fentanyl are achieved quickly in well-perfused tissues such as the lungs, kidneys and brain.
The drug is redistributed to other tissues; it accumulates more slowly in skeletal muscle and yet more slowly in fat, from which it is gradually released into the blood. Up to 80% of fentanyl is bound to plasma proteins.
Fentanyl is primarily metabolised in the liver, probably by N-dealkylation, and it is excreted mainly in the urine with less than 10% representing the unchanged drug. The terminal half-life of fentanyl is 3.7 hours.
5.3 Preclinical Safety Data
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. There are no long-term animal studies to investigate the tumor-forming potential of fentanyl.
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium Chloride, Sodium Hydroxide, Water for Injections.
6.2 Incompatibilities
Fentanyl citrate is incompatible with alkaline solutions (due to reduced solubility) and some drugs.
Published data show that Fentanyl injection is incompatible with alkaline injections including methohexital and thiopental.
Loss of fentanyl citrate due to absorption to PVC containers has been reported when the solution pH was adjusted to the alkaline range (but see section 6.6).
Compatibility must be checked before administration.
6.3 Shelf Life
3 years
6.4 Special Precautions For Storage
Do not store above 25°C.
Keep container in the outer carton.
6.5 Nature And Contents Of Container
2ml/10ml clear One point cut (OPC)glass ampoules, glass type I Ph. Eur. borosilicate glass, packed in cardboard cartons to contain 10 x 2ml/10ml ampoules.
6.6 Special Precautions For Disposal And Other Handling
The injection is for single patient use and should be used immediately after opening. The injection should not be used if particles are present. Any unused portion should be discarded. Fentanyl for infusion may be prepared by dilution with infusion fluids containing 5% glucose or 0.9% sodium chloride.
Fentanyl 5 microgram/ml in 5% glucose or 0.9% sodium chloride exhibited no loss due to sorption to PVC infusion solution containers.
Chemical and physical in-use stability of the diluted product has been demonstrated for 48 hours at 25°C and at 2 - 8°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 - 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Administrative Data
7. Marketing Authorisation Holder
Antigen International Ltd
Roscrea
Co. Tipperary
Ireland
8. Marketing Authorisation Number(S)
PL 02848/0206
9. Date Of First Authorisation/Renewal Of The Authorisation
18 October 1999
10. Date Of Revision Of The Text
31 August 2010
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