Fentanyl 50 micrograms/ml Solution for Injection is an opioid analgesic used:
a. In low doses to provide analgesia during short surgical procedures.
b. In high doses as an analgesic/respiratory depressant in patients requiring assisted
ventilation.
c. In combination with a neuroleptic in the technique of neuroleptanalgesia.
d. In the treatment of severe pain, such as the pain of myocardial infarction

Route of 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).
Intravenous administration either as a bolus or by infusion.
Intramuscular administration.
Fentanyl 50 micrograms/ml Solution for Injection, by the intravenous route, can be
administered to both adults and children. The dose of Fentanyl 50 micrograms/ml Solution
for Injection should be individualised according to age, body weight, physical status,
underlying pathological condition, use of other drugs and type of surgery and anaesthesia.
Adults
The usual dosage regimen in adults is as follows:

                                                     Initial                      Supplemental
Spontaneous Respiration     50-200 mcg              50 mcg
Assisted Ventilation               300-3500 mcg         100-200 mcg

Doses in excess of 200 mcg are for use in anaesthesia only. As a premedicant, 1-2 ml Fentanyl
50 micrograms/ml Solution for Injection may be given intramuscularly 45 minutes before
induction of anaesthesia.
After intravenous administration in unpremedicated adult patients, 2 ml Fentanyl 50
micrograms/ml Solution for Injection may be expected to provide sufficient analgesia for 10-
20 minutes in surgical procedures involving low pain intensity. 10 ml Fentanyl 50 micrograms/ml Solution for Injection 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 mcg/kg Fentanyl 50 micrograms/ml Solution for Injection will
provide intense analgesia for some four to six hours, for intensely stimulating surgery.
Fentanyl 50 micrograms/ml Solution for Injection may also be given as an infusion. In
ventilated patients, a loading dose of Fentanyl 50 micrograms/ml Solution for Injection may
be given as a fast infusion of approximately 1 mcg/kg/min for the first 10 minutes followed
by an infusion of approximately 0.1 mcg/kg/min. Alternatively the loading dose of Fentanyl
50 micrograms/ml Solution for Injection 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, e.g. 0.05-0.08 mcg/kg/minute are necessary if spontaneous ventilation
is to be maintained. Higher infusion rates (up to 3 mcg/kg/minute) have been used in cardiac
surgery.
Fentanyl 50 micrograms/ml Solution for Injection is chemically incompatible with the
induction agents thiopentone and methohexitone because of wide differences in pH.
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 mcg/kg                         1-1.25 mcg/kg
Assisted Ventilation:           2-11 years                    1-3 mcg/kg                         1-1.25 mcg/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 (see section 4.4).
Use in elderly and debilitated patients:
The initial dose should be reduced in the elderly and debilitated patients. The effect of the
initial dose should be taken into account in determining supplemental doses.

Warnings:
Tolerance and dependence may occur. 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.
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 narcotic antagonists (e.g. 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.
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:
− slow IV injection (usually sufficient for lower doses);
− premedication with benzodiazepines;
− use of muscle relaxants.
Non-epileptic (myo)clonic 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.
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.
It is wise to reduce dosage in the elderly and debilitated patients.
In uncontrolled hypothyroidism, pulmonary disease, decreased respiratory reserve,
alcoholism and liver 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.
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.

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.
Administration in labour may cause respiratory depression in the new born infant.
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.
Resuscitation equipment and opioid antagonists should be readily available. Hyperventilation
during anaesthesia may alter the patient's response to CO2, thus affecting respiration
postoperatively.
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.
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., 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.

Effect of other drugs on fentanyl
The use of opioid premedication, barbiturates, benzodiazepines, neuroleptics, halogenic
gases 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 will be
less than usual.

Fentanyl, a high clearance drug, is rapidly and extensively metabolised 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.
Co-administration of fluconazole or voriconazole (moderate CYP3A4 inhibitors) and fentanyl
may result in an increased exposure to fentanyl.
With continuous treatment of fentanyl and concomitant administration of CYP3A4 inhibitors,
a dose reduction of fentanyl may be required to avoid accumulation, which may increase the
risk of prolonged or delayed respiratory depression.
Bradycardia and possibly cardiac arrest can occur when fentanyl is combined with nonvagolytic
muscle relaxants.
The concomitant use of droperidol can result in a higher incidence of hypotension.
Serotonergic Drugs
Coadministration of fentanyl with a serotonergic agent, such as a Selective Serotonin Reuptake
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.

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, Preclinical safety data). The potential risk for humans is unknown.
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 nevertheless administered, an antidote for the child should always be
at hand.
 Pregnancy Category C. No reports linking the use of fentanyl with congenital defects
have been located. Although not teratogenic in rats, fentanyl impaired fertility and
was embryotoxic at IV doses 0.3 times the human dose given for a period of 12 days.
There are no adequate and well-controlled studies in pregnant women. Fentanyl
should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Fentanyl is excreted into human milk. It is therefore recommended that breast-feeding is not
initiated within 24 hours of treatment. The risk/benefit of breast-feeding following fentanyl
administration should be considered.

Where early discharge is envisaged, patients should be advised not to drive or operate
machinery for 24 hours following administration.

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, Table 1 displays ADRs 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 Drug Reactions

(please refer to tabulated info in original SmPC) 

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).
– To reports any side effect(s):
 Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

Symptoms:
The manifestations of fentanyl overdosage 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:
Hypoventilation or apnoea: O2 administration, assisted or controlled respiration.
Respiratory depression: Specific narcotic antagonist (e.g. naloxone). This does not
preclude the use of immediate countermeasures.
The respiratory depression may last longer than the effect of
the antagonist; additional doses of the latter may therefore
be required.
Muscular rigidity: Intravenous neuromuscular blocking agent 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.

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 IV 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 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.

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, Sodium Hydroxide, Water for Injections

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

Protect from light.
Do not store above 25°C.
Keep container in the outer carton.
Keep out of reach and sight of children.

2 ml or 10 ml clear glass ampoules, glass type I Ph Eur borosilicate glass, packed in cardboard
cartons and contain 10 x 2ml/10 ml ampoules.

CD(2), for IV or IM injection.
If only part used, discard the remaining solution.