Pharmaniaga Fentanyl

Pharmaniaga Fentanyl

fentanyl

Manufacturer:

Pharmaniaga LifeScience

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Pharmaniaga Logistics
Full Prescribing Info
Contents
Fentanyl.
Description
Each ampoule of 2 mL contains Fentanyl Citrate 157.10 mcg equivalent to Fentanyl 100 mcg.
The compatible infusion solutions for intravenous use are as follows: Sodium Chloride 0.9% solution; Glucose 5% solution.
The solution should be clear, colourless solution when diluted.
If not required immediately, the diluted solution may be stored up to 24 hours at room temperature (<30°C) and at refrigerated condition (2°C to 8°C) after mixing with the compatible solutions.
Action
Pharmacology: Pharmacodynamics: Fentanyl is a potent opioid analgesic which may be used as an analgesic supplement with general anaesthesia or as an anaesthetic agent alone. Fentanyl possesses μ-agonistic properties.
The agonistic behaviour to δ- and κ-receptors is comparable to morphine. A dose of 100 microgram (2 ml) has an analgesic action which is comparable with 10 mg morphine.
Fentanyl has a rapid onset of action. The maximum analgesic effect and the depressant action on the respiration take place within a few minutes. The average duration of action of the analgesic effect is about 30 minutes after a single bolus injection of 100 microgram.
The level of analgesia is dose related and may be adjusted to the pain level of the surgical procedure.
Fentanyl exhibits relatively small cardio-circulatory effects but has a strong depressive effect on respiration. Stress induced hormonal changes are not reliably suppressed by fentanyl. An increase in blood pressure due to intraoperative pain stimuli may occur in spite of high dose fentanyl treatment.
Depending on dosage and rate of injection, fentanyl may cause muscle rigidity, euphoria, miosis and bradycardia. Intradermal tests and serum determinations of histamine in humans, as well as in-vivo tests in dogs, showed that clinically significant histamine release after fentanyl application is rarely observed.
All effects of fentanyl can be antagonised by specific opioid-antagonists like naloxone.
Pharmacokinetics: After intravenous injection, the fentanyl plasma concentrations decrease rapidly. The disposition of fentanyl is triphasic with half-lifes of about 1 minute, 15 minutes and 6 hours. Fentanyl has a volume of distribution of the central compartment of about 15 litres and a total volume of distribution of about 400 litres.
Especially in elderly patients or after repeated administration, half-lifes may be prolonged. Secondary peak plasma levels may occur.
Fentanyl is bound to plasma proteins for 80-85%.
Fentanyl is metabolised rapidly, mainly in the liver and mainly by oxidative N-desalkylation. The clearance is about 0.5 l/hour/kg. About 75% of the administered dose is eliminated within 24 hours. Only 10% of the dose is excreted as intact substance.
Indications/Uses
Fentanyl is a short acting opioid used as an intravenous analgesic agent in surgical procedures; as an adjunct in the maintenance of general anaesthesia; in combination with a neuroleptic agent in the technique of neuroleptanalgesia; as a respiratory depressant/analgesic in patients requiring prolonged assisted ventilation; for induction of anaesthesia.
Dosage/Direction for Use
Fentanyl should be given only in an environment where the airway can be controlled and by personnel who can control the airway.
The dose of fentanyl is adjusted individually according to age, body weight, physical status, pathological condition, co-medication and as well as type of surgical procedure and type of anaesthesia.
For guidance, the following dosage schedules are proposed. For other special dosage recommendations please refer to the literature.
Neurolept analgesia and neurolept anaesthesia: For neurolept analgesia adults normally will require an initial dose of 50 to 100 micrograms (0.7-1.4 microgram/kg) fentanyl, slowly injected intravenously in combination with a neuroleptic (preferably droperidol). If necessary a second dosage of 50 to 100 micrograms (0.7-1.4 microgram/kg) fentanyl can be given 30 to 45 minutes after the initial dose.
For neurolept anaesthesia under the condition of assisted ventilation adults in general will require an initial dose of 200 to 600 micrograms (2.8-8.4 micrograms/kg) fentanyl slowly injected intravenously in combination with a neuroleptic (preferably droperidol).
The dosage depends on the duration and the severity of the surgical procedure and on the medication used for general anaesthesia. For maintenance of anaesthesia, additional doses of 50 to 100 micrograms (0.7-1.4 microgram/kg) fentanyl can be given every 30 to 45 minutes. The time intervals and doses of these additional administrations have to be adjusted according to the course of the surgical procedure.
Analgesic component in general anaesthesia: Adults: Premedication: 50 to 100 micrograms (1 to 2 mL) fentanyl administered intramuscularly 30 to 60 minutes prior to surgery (modified for high risk patients).
For induction: If fentanyl is used as an analgesic component in general anaesthesia with intubation and ventilation of the patient, in adults initial fentanyl doses of 70-600 microgram (1-8.4 microgram/kg) can be applied as adjunct to general anaesthesia.
For maintenance of analgesia during general anaesthesia, additional doses of 25-100 microgram (0.35-1.4 microgram/kg) fentanyl are to be injected subsequently. The time intervals and the dosage are to be adjusted according to the course of the surgical procedure.
Pain management in the intensive care unit: For use in pain management of ventilated patients in the intensive care unit, the dosage of fentanyl has to be adjusted individually, depending on the course of pain and on concomitant medication. Normally the initial doses are in the range of 50 to 100 micrograms i.v. (0.7-1.4 microgram/kg) but can be titrated higher if necessary.
The initial dose normally is followed by repeated injections, of up to a total of 25 to 125 micrograms fentanyl per hour (0.35-1.8 microgram/kg/h).
Dosage in Paediatric population: Children aged 12 to 17 years should follow the recommended adult dose schedule.
For children aged 2 to 11 years the usual dosage regimen is recommended as follows: See table.

Click on icon to see table/diagram/image

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.
Dosage in elderly and weak patients: The initial dose in elderly and weak patients should be reduced. The effect of the initial dose should be taken into account for the determination of supplemental doses.
Dosage in patients with chronic opioid medication: In patients with chronic opioid medication or with a known history of opioid abuse, a higher dosage of fentanyl may be necessary.
Dosage in patients with additional diseases: In patients with one of the following diseases the intended dosage of fentanyl should be titrated very carefully: uncompensated hypothyreosis; lung diseases, especially those with reduced vital capacity; alcohol abuse; impaired hepatic function; impaired renal function.
Caution is also required if fentanyl is to be administered to patients with adrenal insufficiency, prostatic hypertrophy, porphyria and bradyarrhythmia.
In all these conditions, except alcohol abuse, the dose may have to be reduced. In alcohol abuse, the dose may have to be either reduced or increased.
In these patients a prolonged postoperative monitoring period is recommended.
ROUTE OF ADMINISTRATION: Parenteral [For IV or IM use only.]
Overdosage
Symptoms: Overdosage of fentanyl expresses itself by prolongation of the duration of the pharmacological effects. Dependent on the individual sensitiveness, the clinical picture is respiratory depression ranging from bradypnoea to apnoea, bradycardia up to asystole, decrease in blood pressure, circulatory failure, coma, seizure-like activity, muscle rigidity of the chest wall, trunk and extremities, and pulmonary oedema.
Treatment of overdose: Hypoventilation should be treated by administration of oxygen and the patient should be ventilated. Respiratory depression should be treated by administration of an opioid antagonist like naloxone. The usual initial naloxone dose amounts 0.4 to 2 mg. If no effect can be seen, this dose may be repeated every 2 to 3 minutes up to reversal of respiratory depression or awakening. Since the respiratory depressant effect of fentanyl may last longer than the antagonistic effect, repeated doses of naloxone may be appropriate.
Ventilatory problems caused by muscle rigidity can be diminished or abolished by application of a peripherally acting muscle relaxant. The patient should be monitored carefully. Normal body temperature and balanced fluid volumes should be ensured.
In the case of severe and persistent hypotension, hypovolaemia should be considered, which can be compensated by parenteral fluid therapy.
Contraindications
Fentanyl should not be used in patients with known hypersensitivity to fentanyl, other morphinomimetics or to any of the excipients; respiratory depression without artificial ventilation; a co-medication of MAO inhibitors or within two weeks after cessation of administration of MAO inhibitors; increased intracranial pressure and brain trauma; hypovolaemia and hypotension; myasthenia gravis.
Special Precautions
Intravenous fentanyl should only be used by a trained anaesthetist in hospitals or other locations with facilities for intubation and assisted ventilation.
The vital functions of the patient have to be monitored routinely. This also applies to the postoperative period. Fentanyl has a strong dose dependent depressing effect on respiration which may be prolonged especially in the elderly. In neonates, respiratory depression is to be expected already after small doses. Generally, the risk of a delayed respiratory depression has to be considered. In cases of emergency appropriate instruments and medicinal products have to be available.
In isolated cases, in epileptic patients after a rapid and high dosage fentanyl application (19-36 microgram/kg) of 2 to 5 minutes duration, an electrical seizure activity was recorded electrocorticographically even in healthy brain regions. An impact on the intraoperative electrocorticographic focus localisation after lower fentanyl doses is not known until now.
Muscle rigidity may occur which may also lead to respiratory depression.
The incidence of this rigidity may be decreased by slow intravenous administration.
The reaction can be treated by controlled ventilation and when necessary by administration of a muscle relaxant.
Non-epileptic (myo)clonic reactions may occur.
After administration of fentanyl, an increase of the bile duct pressure and in isolated cases a spasm of the Sphincter of Oddi can be observed: This has to be taken into account during intraoperative diagnostic procedure in bile duct surgery and in pain management of intensive care patients.
As with all other opioids, fentanyl can have an inhibitory effect on intestinal motility. This should be considered in the pain management of intensive care patients with inflammatory or obstructive intestinal diseases.
Bradycardia and asystolia may occur when the patient has received an insufficient dose of an antimuscarinic agent or when fentanyl is combined with non-vagolytic muscle-relaxants. Bradycardia is treated with atropine.
Opioids may cause hypotension, especially in hypovolaemic patients and in patients with decompensated heart failure. Induction doses should be adapted and administered slowly, in order to prevent cardiovascular depression.
Appropriate measures should be taken to maintain a stable arterial pressure.
In neonates, there is a sufficient likelihood of developing a withdrawal syndrome after treatment of more than 5 days or a total dose of >1.6 mg/kg. The use of fast bolus injections of fentanyl should be avoided.
Patients with hepatic failure should be dosed carefully because of the probably disturbed metabolism.
Patients with renal insufficiency should be carefully checked on the symptoms of fentanyl toxicity. As a result of dialysis the volume of distribution of fentanyl may be altered, which can influence the serum concentrations.
When fentanyl is given together with droperidol, the user should be familiar with the specific properties and undesirable effects of both medications.
Effects on ability to drive and use machines: The use of fentanyl may cause a decreased level of reactiveness and concentration. Patients should be advised that the performance of skilled tasks such as driving or operating machinery might be impaired for a considerable time after administration of fentanyl. Patients should be accompanied on their way home after discharge and should be instructed to avoid alcohol.
Use In Pregnancy & Lactation
Pregnancy: There are no sufficient clinical data available to evaluate possible risks of the use of fentanyl during pregnancy. For this reason fentanyl should not be used in this period.
It is advised not to use fentanyl during delivery, because fentanyl passes the placenta and may cause respiratory depression in the neonate.
In obstetrics, fentanyl may only be used intravenously after clamping the umbilical cord. The placental transfer (fetal: maternal ratio) amounts to 0.44 (1.00 : 2.27).
Lactation: Fentanyl passes into breast milk. After the application of fentanyl, breast feeding should be stopped for at least 24 hours.
Side Effects
Respiratory system: Depending on dosage, fentanyl causes respiratory depression up to apnoea, lasting normally only a few minutes at low doses, but many hours at high doses. The respiratory depressant effect may last longer than the analgesic effect and may re-occur in the postoperative period.
Postoperative monitoring is therefore compulsory.
Furthermore, laryngospasm and in single cases bronchospasm was observed. Airway conductance may be impaired by glottic closure through glottic rigidity. In single cases, pulmonary oedema has been described after fentanyl.
Central nervous system: Besides sedation, vertigo, euphoria, nausea and vomiting may also occur.
In rare cases cerebral seizures were observed. Administration of fentanyl over a longer period of time may cause the development of tolerance. The development of drug dependence cannot be ruled out. After infusions of fentanyl of long duration in children, movement disturbances, increased sensitiveness and opioid withdrawal symptoms have been observed.
Cardiovascular system: Fentanyl may cause bradycardia up to cardiac arrest and a decrease in blood pressure, especially in hypovolaemic patients. Bradycardia can be treated by administration of atropine.
Orthostatic regulatory disturbances may occur.
Musculoskeletal system: An increased tension of skeletal muscles (muscle rigidity), especially thoracic stiffness resulting in impaired ventilation can occur, as well as myoclonic movements.
If muscle rigidity is occurring, the application of muscle relaxants is advised.
Various organ systems: The opioid specific effect on smooth muscles may lead to constipation, increased muscle tone of the ureter resulting in urinary retention, especially in patients with prostatic hypertrophy, and spasm of the sphincter of Oddi.
Fentanyl may cause miosis and disturbances of vision.
Allergic reactions like anaphylaxis, pruritus and urticaria may occur.
Sweating and singultus are further side effects which have been observed after the application of fentanyl.
Methemoglobinemia can occur.
Drug Interactions
Agents like barbiturates, benzodiazepines, neuroleptics, volatile anaesthetics containing halogens or other medicaments that have a non-selective depressant effect on the central nervous system (i. e. alcohol), may augment the respiratory depression caused by opioids.
When such medicaments have been administered to patients, the required dose of fentanyl will be lower than usual. This should also result in lowering the dose of other medicaments which have a depressant effect on the central nervous system, when these agents are administered after fentanyl is given.
With higher doses of fentanyl the concomitant application of nitrous oxide or even small doses of diazepam can lead to an impairment of cardiovascular function.
The combined application of fentanyl and midazolam can lead to a decrease in blood pressure.
Simultaneous application of droperidol can lead to a fall in blood pressure, but in some cases a rise in blood pressure was also observed.
The pulmonary arterial pressure can be decreased. Furthermore, shivering, restlessness and postoperative episodes of hallucinations may occur.
In patients with preceding medication with MAO inhibitors within the last 14 days before opioid administration, life-threatening interactions with pethidine on the central nervous system (i.e. agitation, muscle rigidity, hyperpyrexia, convulsions), and the respiratory and circulatory system (i.e. circulatory depression, hypotension, haemodynamic instability and coma) have been observed and cannot be ruled out with fentanyl.
MAO-inhibitors also block the enzymes which metabolise centrally active substances (sedatives, antihistamines, opioids, etc.). As a consequence an intensive and prolonged effect of fentanyl may occur, including respiratory depression.
A preceding administration of cimetidine may lead to increased plasma levels of fentanyl.
Co-administration of clonidine may enhance fentanyl effects and especially prolong fentanyl-induced ventilatory depression.
Vecuronium can cause haemodynamic depression when combined with fentanyl. Significant decreases in heart rate, mean arterial pressure, and cardiac output may occur which are not dependent on the dose of vecuronium.
Bradycardia may develop during the combined application of atracurium and fentanyl.
Fentanyl effects are enhanced and prolonged when combined with baclofen.
Anticonvulsants like carbamazepine, phenytoin, primidone are potent enzyme inducing agents which increase the metabolism of fentanyl by the liver so that fentanyl is cleared from the body more quickly. A marked increase in the fentanyl requirements should be anticipated in any patient on long-term treatment with these anticonvulsants, but not with sodium valproate.
Fentanyl, a high clearance drug, is rapidly and extensively metabolized 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 IV 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. Although clinical data are lacking, in vitro data suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g. fluconazole, ketoconazole, erythromycin, diltiazem and cimetidine) may inhibit the metabolism of fentanyl.
Incompatibilities: This medicinal product must not be diluted with other solutions for parenteral use other than those mentioned in Recommended Dosage.
Compatibility must be checked before administration, if intended to be mixed with other drugs. Fentanyl citrate is reported to be physically incompatible with pentobarbital sodium, methohexital sodium, thiopental sodium and nafcilline.
Storage
Store below 30°C. Protect from light.
Retain in carton until time of use.
Shelf-Life: 3 years.
Following dilution in the recommended diluents, chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (<30°C) and at refrigerated condition (2°C to 8°C). However, from a microbiological point of view, the product should be used immediately.
MIMS Class
ATC Classification
N01AH01 - fentanyl ; Belongs to the class of opioid anesthetics. Used as general anesthetics.
Presentation/Packing
Soln for inj (clear, colourless solution in ampoule) 50 mcg/mL x 2 mL x 10's.
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