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 is also used in the treatment of severe pain, such as that of myocardial infarction.

4.2. Posology and method of administration

Posology

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with Fentanyl in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Adult

The usual dosage regimen is as follows:

Initial micrograms

Supplemental micrograms

Spontaneous Respiration

Assisted ventilation

50 – 200

300 - 3500

50

100 - 200

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 50 micrograms/ml Solution for Injection/Infusion 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.

The dosage of fentanyl should be individualised according to age, body weight, physical status, underlying pathological condition, use of other drugs, and type of surgery and anaesthesia.

The initial dose should be reduced in the elderly and in debilitated patients. The effect of the initial dose should be taken into account in determining supplemental doses.

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:

Age

Initial

Supplemental

Spontaneous respiration

2-11 years

1-3 micrograms/kg

1-1.25 micrograms/kg

Assisted Ventilation

2-11 years

1-3 micrograms/kg

1-1.25 micrograms/kg

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.

Method of administration:

Fentanyl should be given only when 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 50 micrograms/ml Solution for Injection/Infusion can be administered to both adults and children via the intravenous route as a bolus or as an infusion.

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

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.

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.

Serotonin Syndrome

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) 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.

Paediatric population

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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

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 and Opioid use disorder (abuse and dependence)

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses.

Repeated use of opioids may lead to Opioid use disorder (OUD). Abuse or intentional misuse of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

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.

Drug withdrawal syndrome

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

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.

Excipient

This medicine contains less than 1mmol sodium (23mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other drugs on fentanyl

Drugs such as barbiturates, benzodiazepines, neuroleptics, halogenic gases, gabapentinoids (gabapentin and pregabalin) 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.

Diltiazem is another CYP3A4 inhibitor which can cause accumulation of Fentanyl.

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.

Serotonergic Drugs

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.

Effect of fentanyl on other drugs

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.

Sedative medicines such as benzodiazepines or related drugs:

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).

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

Administration to nursing women is not recommended as fentanyl may be secreted in breast milk and may cause respiratory depression in the infant.

Fertility

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).

4.7. Effects on ability to drive and use machines

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 medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8. Undesirable effects

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

System Organ Class

Adverse Drug Reactions

Frequency Category

Very Common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Not Known

(cannot be estimated from the available clinical trial data)

Immune System Disorders

Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, urticaria)

Psychiatric Disorders

Euphoric mood

Delirium

Drug dependence (see section 4.4)

Nervous System Disorders

Dyskinesia;

Sedation;

Dizziness

Headache

Convulsions;

Loss of consciousness;

Myoclonus;

Hyperalgesia

Eye Disorders

Visual disturbance

Cardiac Disorders

Bradycardia;

Tachycardia;

Arrhythmia

Cardiac arrest

Vascular Disorders

Hypotension;

Hypertension;

Vein pain

Phlebitis;

Blood pressure fluctuation

Respiratory, Thoracic and Mediastinal Disorders

Laryngospasm;

Bronchospasm;

Apnoea

Hyperventilation;

Hiccups

Respiratory depression;

Cough

Gastrointestinal Disorders

Nausea;

Vomiting

Dysphagia

Constipation

Skin and Subcutaneous Tissue Disorders

Dermatitis allergic

Pruritus

Musculoskeletal and Connective Tissue Disorder

Muscle Rigidity (which may also involve the thoracic muscles)

General Disorders and Administration Site Conditions

Chills;

Hypothermia,

Drug withdrawal syndrome (see section 4.4)

Injury, Poisoning and Procedural Complications

Confusion postoperative

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 of suspected adverse reactions

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, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

An overdosage 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.

Toxic leukoencephalopathy has been observed with fentanyl overdose.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Management

In the presence of hypoventilation or apnoea, oxygen should be administered and respiration should be assisted or controlled as indicated. A specific narcotic 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.