Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Piramal Critical Care Limited, Suite 4, Ground Floor, Heathrow Boulevard East Wing, 280 Bath Road, West Drayton, UB7 0DQ, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or other opioids.
Respiratory depression, obstructive airways disease.
Concurrent administration with monoamine oxidase inhibitors, or within 2 weeks of their discontinuation.
For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).
Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.
A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.
Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.
Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.
Patients should be closely monitored for signs of misuse, abuse, or addiction.
The clinical need for analgesic treatment should be reviewed regularly.
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with fentanyl.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.
Following intravenous administration of fentanyl, a transient fall in blood pressure may occur, especially in hypovolaemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.
As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early postoperative period. Care should be taken after large doses or infusions of fentanyl to ensure that adequate spontaneous breathing has been established and maintained before discharging the patient from the recovery area.
Significant respiratory depression will occur following the administration of fentanyl in doses in excess of 200 mcg. This, and the other pharmacological effects of fentanyl, can be reversed by specific opioid antagonists, but additional doses may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist.
Resuscitation equipment and opioid antagonists should be readily available. Hyperventilation during anaesthesia may alter the patient’s response to CO2, thus affecting respiration postoperatively.
Administration in labour may cause respiratory depression in the new born infant.
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 antagonised by atropine.
Muscular rigidity (morphine-like effect) may occur.
Rigidity, which may also involve the thoracic muscles, can be avoided by the following measures:
Non-epileptic (myo)clonic movements can occur.
Fentanyl should be given only in an environment where the airway can be controlled and by personnel who can control the airway.
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 transient reduction of the cerebral perfusion pressure.
It is recommended to reduce dosage in the elderly and debilitated patients.
In uncontrolled hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and hepatic or renal impairment the dosage should be titrated with care and prolonged post-operative monitoring is required.
Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.
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 anaesthetic regimen which includes administering intravenous fentanyl.
If fentanyl 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.
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.
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., hyperoreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, rapid discontinuation of fentanyl should be considered.
Concomitant use of fentanyl and CNS depressants especially benzodiazepines or related drugs in spontaneous breathing patients, may increase the risk of profound sedation, respiratory depression, coma and death. If a decision is made to administer fentanyl concomitantly with a CNS depressant, especially a benzodiazepine or a related drug, the lowest effective dose of both drugs should be administered, for the shortest period of concomitant use. Patients should be carefully monitored for signs and symptoms of respiratory depression and profound sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see Interactions).
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.
For Sublimaze 2 and 5 ml ampoules: This medicine contains less than 1 mmol sodium (23 mg) per 2 and 5 ml ampoule, that is to say essentially ‘sodium-free’.
For Sublimaze 10 ml ampoule: This medicinal product contains 35.4 mg sodium per 10 ml ampoule, equivalent to 1.8 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
To be taken into consideration by patients on a controlled sodium diet.
The use of opioid premedication, barbiturates, benzodiazepines or related drugs, neuroleptics, general anaesthetics and other non-selective CNS depressants (e.g. alcohol) may enhance or prolong the respiratory depression of fentanyl.
When patients have received other CNS-depressants, the dose of fentanyl required may be less than usual. Concomitant use with Sublimaze in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death (see warnings and precautions).
Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4. When Sublimaze is used, the concomitant use of a CYP3A4 inhibitor may result in a decrease in fentanyl clearance. With single-dose Sublimaze administration, the period of risk for respiratory depression may be prolonged, which may require special patient care and longer observation. With multiple-dose Sublimaze administration, the risk for acute and/or delayed respiratory depression may be increased, and a dose reduction of Sublimaze may be required to avoid accumulation of fentanyl. Oral ritonavir (a potent CYP3A4 inhibitor) reduced the clearance of a single intravenous 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 Sublimaze dose. Co-administration of other potent or less potent CYP3A4 inhibitors, such as voriconazole or fluconazole, and Sublimaze may also result in an increased and/or prolonged exposure to fentanyl.
Bradycardia and possibly cardiac arrest can occur when fentanyl is combined with non-vagolytic muscle relaxants.
Coadministration 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 (see section 4.3 Contraindications).
Following the administration of 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 or related drugs, during this period may disproportionally increase the risk for respiratory depression (see warnings and precautions).
Plasma concentrations of etomidate increased considerably (by a factor 2-3) when combined with fentanyl. The total plasma clearance and volume of distribution of etomidate is decreased by a factor of 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.
Fentanyl can cross the placenta in early pregnancy. Studies in animals have shown some reproductive toxicity (see Section 5.3, Preclinical safety data).
Administration during childbirth (including Caesarean section) is not recommended because fentanyl crosses the placenta and may suppress spontaneous respiration in the newborn period. If fentanyl 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.
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.
Administration to nursing women is not recommended as fentanyl may be secreted in breast milk and may cause respiratory depression in the infant.The risk/benefit of breast-feeding following fentanyl administration should be considered.
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 section 5.3 Preclinical safety data).
Where early discharge is envisaged, patients should be advised not to drive or operate machinery for at least 24 hours following administration.
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 anaesthetic. 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 Reactions 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 adverse reactions, Table 1 displays adverse reactions that have been reported with the use of fentanyl IV from either clinical trials or postmarketing experience.
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 Reactions:
| System Organ Class | Adverse Reactions | |||
|---|---|---|---|---|
| Frequency Category | ||||
| Very Common (≥1/10) | Common (≥1/100 to <1/10) | Uncommon (≥1/1,000 to <1/100) | Not Known | |
| Immune System Disorders | Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, urticaria) | |||
| Psychiatric Disorders | Agitation | Euphoric mood | Delirium Drug dependence (see section 4.4) | |
| Nervous System Disorders | Muscle rigidity (which may also involve the thoracic muscles) | Dyskinesia; Sedation; Dizziness | Headache | Convulsions; Loss of consciousness; Myoclonus |
| Eye Disorders | Visual disturbance | |||
| Cardiac Disorders | Bradycardia; Tachycardia; Arrhythmia | Cardiac arrest | ||
| Vascular Disorders | Hypotension; Hypertension; Venous pain | Phlebitis; Blood pressure fluctuation | ||
| Respiratory, Thoracic and Mediastinal Disorders | Laryngospasm; Bronchospasm; Apnoea | Hyperventilation; Hiccups | Respiratory depression | |
| Gastrointestinal Disorders | Nausea; Vomiting | |||
| Skin and Subcutaneous Tissue Disorders | Allergic dermatitis | Pruritus | ||
| General Disorders and Administration Site Conditions | Chills; Hypothermia Drug withdrawal syndrome | Drug withdrawal syndrome (see section 4.4) | ||
| Injury, Poisoning and Procedural Complications/b> | Postoperative confusion | Airway complication of anaesthesia | ||
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.
The product is chemically incompatible with the induction agents thiopentone and methohexitone because of the wide differences in pH.
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