Fentanyl is an opioid analgesic used:

-            In low doses to provide analgesia during short surgical procedures. -          In high doses as an analgesic/respiratory depressant in patients requiring assisted ventilation.

-            In combination with a neuroleptic in the technique of neuroleptanalgesia.

-            In the treatment of severe pain, such as the pain of myocardial infarction.

Method of administration:

Intravenous administration either as a bolus or by infusion.

Intramuscular 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).

Fentanyl, by the intravenous route, can be administered to both adults and children. The dose should be individualised according to age, bodyweight, physical status, underlying pathological condition, use of other drugs and type of surgery and anaesthesia.

To avoid bradycardia, it is recommended to administer a small intravenous dose of an anti-cholinergic just before anaesthetic induction.

It is recommended to wear gloves while opening the ampoule (see section 6.6 Special precautions for disposal and other handling).

The usual dosage regimen is as follows:

Pediatric population

Children aged 12 to 17 years old-follow adult dosage:

Children aged 2 to 11 years old:

Techniques that involve analgesia in a spontaneous breathing child should only be used as part of an anesthetic 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 (see section 4.4).

Doses in excess of 200 micrograms are for use in anaesthesia only. As a premedicant, 1-2 ml fentanyl may be given intramuscularly 45 minutes before induction of anaesthesia.

After intravenous administration in unpremedicated adult patients, 2 ml fentanyl may be expected to provide sufficient analgesia for 10-20 minutes in surgical procedures involving low pain intensity. 10 ml fentanyl injected as a bolus gives analgesia lasting about one hour. The analgesia produced is sufficient for surgery involving moderately painful procedures. Giving a dose of 50 micrograms /kg fentanyl will provide intense analgesia for some four to six hours, for intensely stimulating surgery.

Fentanyl may also be given as an infusion. In ventilated patients, a loading dose of fentanyl may be given as a fast infusion of approximately 1 microgram/kg/minute for the first 10 minutes followed by an infusion of approximately 0.1 micrograms /kg/minute. Alternatively, the loading dose of fentanyl may be given as a bolus. Infusion rates should be titrated to individual patient response; lower infusion rates may be adequate. Unless it is planned to ventilate post-operatively, the infusion should be terminated at about 40 minutes before the end of surgery.

Lower infusion rates, eg 0.05-0.08 micrograms /kg/minute are necessary if spontaneous ventilation is to be maintained. Higher infusion rates (up to 3 micrograms /kg/minute) have been used in cardiac surgery.

Fentanyl is chemically incompatible with the induction agents thiopentone and methohexitone because of wide differences in pH.

Use in elderly and debilitated patients:

It is wise to reduce the dosage in the elderly and debilitated patients. The effect of the initial dose should be taken into account in determining supplemental doses.

Obese patients:

                        In obese patients there is a risk of overdosing if the dose is calculated based on body weight. Obese patients should have dosage calculated according to their estimated lean body mass.

Renal Impairment

                        In patients with renal impairment reduced dosing of fentanyl should be considered and these patients should be observed carefully for signs of fentanyl toxicity (see section 5.2 Pharmacokinetic properties).

Fentanyl is controlled under the Misuse of Drugs Act 1971 (Schedule 2).

Fentanyl should be used with great caution in patients with acute alcoholism, head injuries and raised intracranial pressure.

Tolerance and dependence may occur.

                          Cardiac warnings

Bradycardia and possibly asystole can occur in non-atropinised patients, and can be  antagonised by atropine.

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.

                          Muscle rigidity

Muscular rigidity (morphine-like effect) may occur. Rigidity, which may also involve  the thoracic muscles, can be avoided by the following measures:

-                   slow intravenous injection (usually sufficient for lower doses);

-                   premedication with benzodiazepines;

-                   use of muscle relaxants.

Non-epileptic myoclonic movements can occur.

Precautions:

Fentanyl should be given only in an environment where the airway can be controlled and by personnel who can control the airway.

                          Myasthenia gravis

As with all opioid analgesics, care should be observed when administering fentanyl to patients with myasthenia gravis.

                          Special dosage conditions

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 wise to reduce the dosage in the elderly and debilitated patients (see 4.2 Posology and Method of Administration).

In hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and liver or renal impairment, the dosage should be titrated with care and prolonged monitoring may be required.

Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.

Drug withdrawal symptoms may occur on discontinuation of treatment.  Withdrawal symptoms may also occur in neonates of opioid-dependent mothers.

                                        Labour

Administration of opioid analgesics during labour may cause respiratory depression in the perinatal child and may cause gastric stasis and increase the risk of inhalation pneumonia in the mother.

                         Interaction with neuroleptics

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 a higher incidence of hypotension.   Neuroleptics   can   induce   extrapyramidal   symptoms   that   can   be controlled with anti-Parkinson agents.

Bile duct

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.

                                        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.   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 micrograms.   This, and the other pharmacological effects of fentanyl, can be reversed by specific narcotic antagonists (eg naloxone).   Additional doses of the latter 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 carbon dioxide, thus affecting respiration postoperatively.

Serotonin Syndrome

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.

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.

Fentanyl contains sodium. To be taken into consideration by patients on a controlled sodium diet.

Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly  by CYP3A4.

                          Monoamine Oxidase Inhibitors

The concurrent use of MAOIs (including moclobemide) is contra-indicated (see 4.3 Contra-indications) as they may result in an unpredictable, severe and occasionally fatal reaction, consisting of excitation, sweating, rigidity,

                          hypertension, respiratory depression, seizures and hyperpyrexia.

                          CNS depressants

CNS depressants such as alcohol, hypnotics, anxiolytics and sedatives, barbiturates, neuroleptics, halogenic gases and tricyclic antidepressants may enhance or prolong the respiratory depression effects of fentanyl as well as increasing the general depressant effects. When patients have received CNS- depressants, the dose of fentanyl required may, therefore, be less than usual.

Similarly, the dose of other CNS-depressant drugs should be reduced following           the administration of fentanyl.

                          Opioid agonists

Additive effects on CNS depression, respiratory depression and hypotension can occur with concomitant use of opioid agonist analgesics.

Co-administration of fluconazole or voriconazole (moderate CYP3A4 inhibitors) and fentanyl may result in an increased exposure to fentanyl.

However, buprenorphine may antagonise the analgesic effect of previously                   administered opioids and concomitant use is generally not recommended.

                          Muscle relaxants

Bradycardia and possibly asystole can occur when fentanyl is combined with     non-vagolytic muscle relaxants.

                          Anti-virals

Oral ritonavir reduced the clearance of intravenous fentanyl by two thirds; however, peak plasma concentrations after a single dose of intravenous 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, dose reduction of fentanyl may be required to avoid accumulation of fentanyl, which may increase the risk of prolonged or delayed  respiratory depression.

                          Anti-fungals

Itraconazole (a potent CYP3A4 inhibitor) at 200mg/day given orally for 4                   days had no significant effect on the pharmacokinetics of intravenous fentanyl.

                          Histamine H2 antagonists

Cimetidine can reduce the metabolism of opioid analgesics resulting in                   increased plasma concentration.

                          Neuroleptics

The concomitant use of droperidol can result in a higher incidence of                   hypotension.

                         Anti-emetics

The effects of metoclopramide or domperidone on gastro-intestinal activity is            antagonised by opioid analgesics.

                          Effects on other drugs

The plasma levels of ciprofloxacin may be reduced in the presence of opiate premedicants. Plasma levels of mexiletine may also be reduced in the presence      of opioid analgesics.

Serotonergic Drugs

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.

Effect of fentanyl on other drugs

Following the administration of fentanyl, the dose of other CNS depressant drugs should be reduced.

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 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.

Pregnancy

Although no teratogenic or acute embryotoxic effects have been observed in animal experiments, insufficient data are available to evaluate any harmful effects in humans. As with other drugs, possible risks should be weighed against potential benefits to the patient.

Administration during childbirth (including Caesarean section) is not recommended because fentanyl crosses the placenta and the foetal respiratory centre is particularly sensitive to opioids.   If fentanyl is administered, an antidote for the child should always  be  at  hand.    The  mother  is  also  at  risk  of  gastric  stasis  and  inhalation pneumonia  if  an  opioid  analgesic  is  administered  during  labour.    Withdrawal symptoms may occur in neonates of dependent mothers. Studies in animals have shown some reproductive toxicity.

                          Breast-feeding

Fentanyl  may  enter  breast  milk  and  although  only  low  levels  may  occur,  it  is recommended that breast feeding is not initiated within 24 hours of treatment.

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).

Where early discharge is envisaged, patients should be advised not to drive or operate machinery for 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 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:

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

-         You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and - It was not affecting your ability to drive safely.

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 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 post marketing experiences.

When a neuroleptic such as droperidol is used with fentanyl, the following adverse reactions may be observed: chills and/or shivering, restlessness, post-operative hallucinatory episodes and extrapyramidal symptoms.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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:

The National Pharmacovigilance and Drug Safety Centre (NPC)               o Fax: +966-11-205-7662           o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.             o Toll free phone: 8002490000        o E-mail: npc.drug@sfda.gov.sa            o Website: www.sfda.gov.sa/npc          

Symptoms:

The manifestations of fentanyl over dosage are generally an extension of its pharmacological action. Depending on the individual sensitivity, the clinical picture is determined primarily by the degree of respiratory depression, which varies from bradypnoea to apnoea.

Treatment:

Treatment is supportive.

If there is hypoventilation or apnoea, a patent airway must be established, oxygen should be given and the requirement for assisted or controlled ventilation should be assessed. Narcotic antagonists may be required if there is evidence of significant respiratory or cardiovascular depression. Naloxone should be given intravenously as soon as possible and repeated every 2-3 minutes if necessary (refer to naloxone product literature for details). Intravenous neuromuscular blocking agents may be given if muscular rigidity is present. Intravenous fluids and other supportive measures should be employed as indicated.

Pharmacotherapeutic group:

Analgesics –derivatives.  ATC code: N02A B03 General Anaesthetics.  ATC code: N01A H01

Fentanyl is a synthetic opiate with a clinical potency of 50 to 100 times that of morphine.  Its onset of action is rapid and its duration of action is short.  In man, a single intravenous dose of 0.5-1 mg/70 kg body weight immediately produces a pronounced state of surgical analgesia, respiratory depression, bradycardia and other typical morphine-like effects.  The duration of action of the peak effects is about 30 minutes.  All potent morphine-like drugs produce relief from pain, ventilatory depression, emesis, constipation, physical dependence, certain vagal effects and varying degrees of sedation.  Fentanyl, however, differs from morphine not only by its short duration of action but also by its lack of emetic effect and minimal release of histamine and hypotensive activity in animals.

Some pharmacokinetic parameters for fentanyl are as follows:

Urinary excretion = 8%

Bound in plasma = 80%

Clearance (ml/min/kg) = 13±2

Volume of distribution (litres/kg) = 4.0±0.4

Estimates of terminal half-life range from 141 to 853 minutes.

Fentanyl is rapidly absorbed following intramuscular injection, however, there are wide inter-individual variations.

Fentanyl is rapidly and extensively metabolized in the liver mainly by CYP3A4 enzymes. The metabolites are considered to be inactive.

Fentanyl crosses the placenta and is excreted in breast milk.

Renal impairment

Data obtained from a study administering IV fentanyl in patients undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population. If patients with renal impairment receive fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.2 Posology and method of administration).

Obese Patients

An increase in clearance of fentanyl is observed with increased body weight. In patients with a BMI >30, clearance of fentanyl increases by approximately 10% per 10 kg increase of the fat free mass (lean body mass).

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. In a two-year rat bioassay, fentanyl was not carcinogenic.

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.

Sodium chloride

Water for injections

The product is chemically incompatible with the induction agents thiopentone and methohexitone because of the wide differences in pH.

Store below 30C. Do not refrigerate or freeze. 

Keep the container in the outer carton.

2ml and 10ml clear glass (Ph. Eur. Type I) ampoules containing 2ml or 10ml solution for injection.

Pack size: 10 ampoules per carton or 5 ampoules per carton.

Fentanyl is controlled under the Misuse of Drugs Act 1971 (Schedule 2).

Wear gloves while opening ampoule.

Accidental dermal exposure should be treated by rinsing the affected area with water.

Avoid usage of soap, alcohol, and other cleaning materials that may cause chemical or physical abrasions to the skin.