Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mercury Pharmaceuticals Limited, Capital House, 85 King William Street, London EC4N 7BL, UK
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Known intolerance to fentanyl or other morphino-mimetics.
Respiratory depression.
Obstructive airways disease.
In patients after operative interventions in the biliary tract.
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 potent opioids.
Respiratory depression is dose related and can be reversed by a specific narcotic antagonist such as naloxone, but additional doses of the latter 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 anaesthesia may alter the patient’s response to CO2, thus affecting respiration post-operatively.
Induction of muscle rigidity, which may also involve the thoracic muscles, can occur, but can be avoided by the following measures: slow I.V. injection (ordinarily sufficient for lower doses), premedication with benzodiazepines and the use of muscle relaxants.
Non-epileptic (myo)clonic movement can occur.
Bradycardia, and possibly cardiac arrest, can occur if the patient has received an insufficient amount of anticholinergic, or when fentanyl is combined with non-vagolytic muscle relaxants. Bradycardia can be treated with atropine.
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 50 micrograms/ml Solution for Injection/Infusion have been administered.
Repeated use of fentanyl may result in the development of tolerance and dependence.
Opioids may induce hypotension, especially in hypovolemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.
The use of rapid bolus injection of opioids should be avoided in patients with compromised intracerebral compliance; in such patient 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 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 renal or hepatic function. Such patients also require prolonged postoperative monitoring.
If fentanyl is administered with a neuroleptic [such as droperidol], 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 higher incidence of hypotension. Neuroleptics can induce extrapyramidal symptoms that can be controlled with anti-Parkinson agents.
As with other opioids, due to the anticholinergic effects, administration of fentanyl may lead to increases of bile duct pressure and, in isolated cases, spasms of the sphincter of Oddi might be observed.
In patients with myasthenia gravis, careful consideration should be applied in the use of certain anticholinergic agents and neuromuscular-blocking pharmaceutical agents prior to, and during, the administration of a general anesthetics regimen which includes administering intravenous fentanyl.
Administration of fentanyl during labour may result in neonatal respiratory depression.
Caution is advised when fentanyl is coadministered 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, diarrhoea).
If serotonin syndrome is suspected, rapid discontinuation of fentanyl should be considered.
Techniques that involve analgesia in a spontaneously 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.
Concomitant use of Fentanyl and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Fentanyl concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids. Risks are increased in patients with a personal history of substance abuse (including drug or alcohol abuse or addiction).
Repeated administration at short term intervals for prolonged periods may result in the development of withdrawal syndrome after cessation of therapy, which may manifest by the occurrence of the following side effects: nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating.
Drugs such as barbiturates, benzodiazepines, neuroleptics, halogenic gases, and other non-selective CNS depressants (e.g. alcohol) may potentiate the respiratory depression of narcotics.
When patients have received such drugs, the dose of fentanyl required will be less than usual.
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 I.V. fentanyl.
Co-administration of fluconazole or voriconazole and fentanyl may result in an increased exposure to fentanyl.
Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of I.V. fentanyl by two thirds; however, peak plasma concentrations after a single dose of I.V. 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.
With continuous treatment of fentanyl and concomitant administration of CYP3A4 inhibitors a dose reduction of fentanyl may be required to avoid accumulation of fentanyl, which may increase the risk of prolonged or delayed respiratory depression.
It is usually recommended to discontinue MAO-inhibitors 2 weeks prior to any surgical or anesthetic procedure. However, several reports describe the uneventful use of fentanyl during surgical or anaesthetic procedures in patients on MAO- inhibitors.
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.
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.
Co-administration of fentanyl with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or 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.
Following the administration of fentanyl, the dose of other CNS depressant drugs should be reduced.
Plasma concentration of etomidate increased considerably (by a factor 2 to 3) when combined with fentanyl. The total plasma clearance and volume of distribution of etomidate are 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.
The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
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. (See section 5.3). The potential risk for humans is unknown.
I.M. or I.V. administration during childbirth, (including caesarean section) is not recommended because Fentanyl crosses the placenta and because the foetal respiratory centre is particularly sensitive to opiates. If fentanyl is nevertheless administered, an antidote for the child should always be at hand.
Fentanyl is excreted into human milk. Therefore, nursing is not recommended for 24 hours following the administration of this drug. The risk/benefit of breast-feeding following fentanyl administration should be considered.
Fentanyl has a moderate influence on the ability to drive and use machines. Patients should only drive or operate a machine if sufficient time has elapsed after the administration of fentanyl.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
The safety of fentanyl IV was evaluated in 376 subjects who participated in 20 clinical trials evaluating fentanyl IV as an anesthetic. These subjects took at least 1 dose of fentanyl IV and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (≥5% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): Nausea (26.1); Vomiting (18.6); Muscle Rigidity (10.4); Hypotension (8.8); Hypertension (8.8); Bradycardia (6.1); and Sedation (5.3).
Including the above-mentioned ADRs, 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 (≥ 1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).
Table 1. Adverse Drug Reactions:
Not Known: Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, urticaria)
Uncommon: Euphoric mood
Not Known: Delirium
Common: Dyskinesia; Sedation; Dizziness
Uncommon: Headache
Not Known: Convulsions; Loss of consciousness; Myoclonus; Hyperalgesia
Common: Visual disturbance
Common: Bradycardia; Tachycardia; Arrhythmia
Cardiac arrest
Common: Hypotension; Hypertension; Vein pain
Uncommon: Phlebitis; Blood pressure fluctuation
Common: Laryngospasm; Bronchospasm; Apnoea
Uncommon: Hyperventilation; Hiccups
Not Known: Respiratory depression; Cough
Very Common: Nausea; Vomiting
Not Known: Constipation
Common: Dermatitis allergic
Not Known: Pruritus
Very Common: Muscle Rigidity (which may also involve the thoracic muscles)
Uncommon: Chills; Hypothermia
Not Known: Drug withdrawal syndrome (see section 4.4)
Common: Confusion postoperative
Uncommon: Airway complication of anaesthesia; Agitation postoperative
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).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Fentanyl citrate is incompatible with alkaline solutions (due to reduced solubility) and some drugs.
Published data show that Fentanyl 50 micrograms/ml Solution for Injection/Infusion 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.
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