Consumer medicine information

Fentanyl Juno Injection

Fentanyl

BRAND INFORMATION

Brand name

Fentanyl Juno

Active ingredient

Fentanyl

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fentanyl Juno Injection.

SUMMARY CMI

Fentanyl Juno Injection

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I being treated with Fentanyl Juno Injection?

Fentanyl Juno Injection contains the active ingredient fentanyl citrate. Fentanyl Juno Injection is a short-term pain reliever that belongs to a group of medicines called opioid analgesics. It is most commonly used to relieve severe pain. It may also be used just before, or during, an operation, to help the anaesthetic work better.

For more information, see Section 1. Why am I being treated with Fentanyl Juno Injection? in the full CMI.

2. What should I know before treatment with Fentanyl Juno Injection?

Do not use if you have ever had an allergic reaction to fentanyl or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before treatment with Fentanyl Juno Injection? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fentanyl Juno Injection and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Fentanyl Juno Injection given?

Your doctor will decide what dose of fentanyl you will receive. This depends on your age, physical condition and other factors, such as your weight.

More instructions can be found in Section 4. How is Fentanyl Juno Injection given? in the full CMI.

5. What should I know during treatment with Fentanyl Juno Injection?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are being given fentanyl.
  • If you become pregnant while you are being treated with fentanyl, tell your doctor immediately.
Things you should not do
  • Do not stop using this medicine suddenly. If you have been using fentanyl for more than two weeks, you may experience unpleasant feelings if you stop fentanyl suddenly.
Driving or using machines
  • Do not drive a car, operate machinery, or do anything else that could be dangerous until you know how fentanyl affects you. Fentanyl may cause drowsiness and impair coordination.
Drinking alcohol
  • Do not drink alcohol while you are being treated with fentanyl.
Looking after your medicine
  • If you are being given Fentanyl Juno Injection while in hospital, it will be stored in the pharmacy or on the ward. Store below 25°C.

For more information, see Section 5. What should I know during treatment with Fentanyl Juno Injection? in the full CMI.

6. Are there any side effects?

Common side effects include sweating, dizziness, faintness, nausea or vomiting. Tell your doctor immediately if you notice slow or troubled breathing, muscle stiffness, slowed heart rate, blurred vision, spasm of the larynx (voice box) or itching. If you experience serious side effects such as allergic reactions, agitation, hallucinations, twitching or loss of coordination, severe dizziness and weakness, irregular heart rate, changes in blood pressure, skin turning blue or unconsciousness, you may need urgent medical attention or hospitalisation.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING:

Limitations of use

Fentanyl Juno Injection should only be used when your doctor decides that other treatment options are not able to effectively manage your pain or you cannot tolerate them.

Hazardous and harmful use

Fentanyl Juno Injection poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment.

Life threatening breathing problems

Fentanyl Juno Injection can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing) even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting fentanyl and after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate.

Use of other medicines while using fentanyl

Using fentanyl with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentinoids (e.g. gabapentin and pregabalin), cannabis and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. Your doctor will minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while using fentanyl.



FULL CMI

Fentanyl Juno Injection

Active ingredient(s): fentanyl citrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Fentanyl Juno Injection. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Fentanyl Juno Injection.

Where to find information in this leaflet:

1. Why am I being treated with Fentanyl Juno Injection?
2. What should I know before treatment with Fentanyl Juno Injection?
3. What if I am taking other medicines?
4. How is Fentanyl Juno Injection given?
5. What should I know during treatment with Fentanyl Juno Injection?
6. Are there any side effects?
7. Product details

1. Why am I being treated with Fentanyl Juno Injection?

Fentanyl Juno Injection contains the active ingredient fentanyl citrate. Fentanyl Juno Injection is a short-term pain reliever that belongs to a group of medicines called opioid analgesics. Fentanyl acts in the brain and spinal cord. It works quickly to reduce pain and its effects wear off quickly.

Fentanyl may be used alone but is usually used in hospital with other anaesthetics or with a sedative such as droperidol before an operation to provide an anaesthetic effect and during an operation to help continue the anaesthesia.

Your doctor may have prescribed it for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

2. What should I know before treatment with Fentanyl Juno Injection?

If you are not sure whether you should be given this medicine, talk to your doctor or pharmacist.

Warnings

Do not use Fentanyl Juno Injection if you:

  • are allergic to fentanyl, or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin.
    Always check the ingredients to make sure you can use this medicine.
  • have bronchial asthma or severe disease relating to the lungs
  • have breathing difficulties or shallow breathing
  • are undergoing treatment with monoamine oxidase (MAO) inhibitors (e.g. phenelzine, tranylcypromine, moclobemide or selegiline) or have stopped MAO inhibitor treatment during the last fourteen days
  • have myasthenia gravis (severe muscle weakness)
  • have long-standing pain not related to cancer.

Check with your doctor if you:

  • have or have had any other medical conditions, especially the following:
    - kidney or liver problems
    - lung or breathing problems
    - slow or irregular heartbeats; heart problems
    - snoring or sleep apnoea (you temporarily stop breathing or have difficulty breathing while asleep)
    - recent head injury
  • take any medicines for any other condition
  • have allergies to any other medicines, foods, preservatives or dyes.
  • or someone in your family have a history of drug and alcohol abuse or mental illness
  • are a smoker

If you have not told your doctor or pharmacist about any of the above, tell them before you are given Fentanyl Juno Injection.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

As fentanyl crosses the placenta, your doctor or pharmacist will discuss the possible risks and benefits of you being given Fentanyl Juno Injection during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

As fentanyl may pass into breast milk, breastfeeding is not recommended for 24 hours following use of Fentanyl Juno Injection. Your doctor or pharmacist will discuss the possible risks and benefits of being given Fentanyl Juno Injection during breastfeeding.

Children

Fentanyl Juno Injection should not be given to children under the age of 2 years. There is not enough information to recommend the use of this medicine for children under the age of 2 years.

Addiction

You can become addicted to fentanyl even if you use it exactly as prescribed. Fentanyl may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence

As with all other opioid containing products, your body may become used to you using fentanyl. Using it for a long time (i.e. more than two weeks) may result in physical dependence (i.e. it can be habit-forming or addictive). Physical dependence means that you may experience withdrawal symptoms if you stop using fentanyl suddenly, so it is important to use it exactly as directed by your doctor.

However, it is also important to keep your pain under control. Your doctor can advise you on how to manage this.

Tolerance

Tolerance to fentanyl may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Withdrawal

Continue using your medicine for as long as your doctor tells you. If you stop using this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating.

Fentanyl Injection given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Fentanyl Juno Injection and affect how it works. These include:

  • barbiturates
  • general anaesthetics and strong pain killers (e.g. lidocaine and opioid analgesics)
  • sedating antipsychotics (e.g. droperidol, chlorpromazine, fluphenazine and thioridazine) and centrally-active anti-emetics (e.g. metoclopramide and promethazine)
  • benzodiazepines (and other medicines) to treat anxiety, acute stress reactions, agitation, tremor, such as diazepam, alprazolam, lorazepam or midazolam
  • other medicines which may make you drowsy such as sleeping tablets, tablets to calm your nerves, sedatives, tranquilisers, hypnotics and muscle relaxants
  • antidepressants or medicines for anxiety disorders such as:
    - selective serotonin re-uptake inhibitors (SSRIs)
    - serotonin norepinephrine reuptake inhibitors (SNRIs)
    - monoamine oxidase (MAO) inhibitors (e.g. phenelzine, tranylcypromine and moclobemide)
  • MAO inhibitor used to treat Parkinson's disease e.g. selegiline, rasagiline and safinamide.
  • medicines to treat mental disorders
  • medicines to treat seizures (gabapentinoids e.g. gabapentin, pregabalin)

Medicines that may increase the effect of Fentanyl Injection include:

  • macrolide antibiotics (e.g. erythromycin)
  • azole-antifungal agents (e.g. ketoconizole)
  • protease inhibitors or medication for HIV (e.g. ritonavir)

Medicines that may reduce the effect of Fentanyl Injection include:

  • rifampin (anti-tuberculosis medication)
  • carbamazepine and phenytoin, medicines used to control fits or seizures.

These medicines may be affected by Fentanyl Juno Injection or may affect how well it works. You may need different amounts of your medicine, or different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while you are being given this medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Fentanyl Juno Injection.

4. How is Fentanyl Juno Injection given?

How much is given

  • Your doctor will decide what dose you will receive. This depends on your age, physical condition and other factors, such as your weight.

How is it given

  • Your doctor or nurse will usually give Fentanyl Juno Injection to you.
  • Fentanyl Juno Injection is given as an injection into a vein or muscle.

If you are given too much Fentanyl Juno Injection (overdose)

Fentanyl Juno Injection is administered under the care of a highly trained doctor so overdose rarely occurs.

However, if you or someone else receive too much (overdose), and experience one or more of the symptoms below, urgent medical attention is required. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used Fentanyl Injection that was prescribed for you.

Symptoms of an overdose may include:

  • slow, unusual or difficult breathing causing skin to turn blue
  • severe drowsiness, dizziness or unconsciousness
  • slow or weak heartbeat, decreases in heart rate and blood pressure
  • nausea or vomiting
  • convulsions or fits
  • severe weakness or muscle stiffness
  • a brain disorder (known as toxic leukoencephalopathy)

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know during treatment with Fentanyl Juno Injection?

Things you should do

  • Tell any other doctors, dentists and pharmacists who are treating you that you are being given Fentanyl Juno Injection.
  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given Fentanyl Juno Injection.
  • If you plan to have surgery that needs a local or general anaesthetic, tell your doctor or dentist you are being given Fentanyl Juno Injection.
  • If you become pregnant while you are being treated with Fentanyl Juno Injection, tell your doctor or pharmacist.
  • Tell your doctor, pharmacist or nurse if you have any concerns about being given Fentanyl Juno Injection.

Things you should not do

  • Do not give Fentanyl Juno Injection to anyone else, even if they have the same condition as you.
  • Do not use Fentanyl Juno Injection to treat any other complaints unless your doctor tells you to.
  • Do not stop using Fentanyl Juno Injection, or lower the dosage, without checking with your doctor or pharmacist.
  • Do not take any other medicines, whether they are prescription or over-the-counter medicines, unless they have been prescribed or recommended by a doctor or pharmacist who knows you are being treated with Fentanyl Juno Injection.
  • Avoid smoking or taking other drugs unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Fentanyl Juno Injection affects you.

Fentanyl Juno Injection may cause feelings of weakness, dizziness, drowsiness and impairment of coordination in some people. Do not drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy or feeling uncoordinated.

Drinking alcohol

Tell your doctor if you drink alcohol.

Do not drink alcohol while you are undergoing treatment with fentanyl unless otherwise advised by your doctor or pharmacist as drowsiness and coordination impairment may be worse.

Looking after your medicine

If you are being given Fentanyl Juno Injection while in hospital, it will be stored in the pharmacy or on the ward.

Fentanyl Juno Injection should be stored in a cool, dry place, protected from light where the temperature stays below 25°C.

Do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Do not use this medicine after the expiry date.

Fentanyl Juno Injection should not be given to you if the packaging is torn or shows signs of tampering.

Getting rid of any unwanted medicine

If your doctor tells you to stop using this medicine or the expiry date as passed, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effectsWhat to do
  • sweating
  • dizziness, faintness
  • nausea, vomiting
  • difficulty swallowing
Speak to your doctor if you have any of these common serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • agitation, hallucinations
  • slow or troubled breathing
  • muscle stiffness, twitching or loss of coordination
  • severe dizziness and weakness
  • slow, fast or irregular heart rate
  • blurred vision
  • increase or decrease in blood pressure
  • skin turning blue and clammy
  • unconsciousness
  • spasm of the larynx (voice box)
  • allergic reactions
  • itching
The following side effects may occur when a sedating medicine (e.g. droperidol) is used with Fentanyl Juno Injection
  • chills, shivering
  • restlessness
  • drowsiness
  • short periods of depression
  • imaginary events
  • uncontrolled movement of the y or eyes
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Tell your doctor immediately if you experience any of these symptoms.
You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Tell your doctor immediately if you have unwanted side effects which continue after your treatment has stopped.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Fentanyl Juno Injection contains

Active ingredient
(main ingredient)		Fentanyl citrate
Other ingredients
(inactive ingredients)		Sodium hydroxide
Sodium chloride
Water for injections

Do not take this medicine if you are allergic to any of these ingredients.

Fentanyl Juno Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

What Fentanyl Juno Injection looks like

Fentanyl Juno Injection is a sterile, aqueous, preservative-free, colourless or almost colourless solution in glass ampoules.

It is available in the following strengths and pack sizes:

  • 100 micrograms / 2 mL x 5 ampoules AUST R 384587
  • 500 micrograms / 10 mL x 5 ampoules AUST R 384588

Who distributes Fentanyl Juno Injection

Juno Pharmaceuticals Pty Ltd,
15-17 Chapel St,
Cremorne,
VIC, 3121

www.junopharm.com.au

This leaflet was prepared in November 2024.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

Fentanyl Juno

Active ingredient

Fentanyl

Schedule

S8

 

1 Name of Medicine

Fentanyl citrate.

2 Qualitative and Quantitative Composition

2 mL sterile solution of pH 4.0 - 7.5 containing 100 microgram of fentanyl (as citrate).
10 mL sterile solution of pH 4.0 - 6.5 containing 500 microgram of fentanyl (as citrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Injection solution. Clear, colourless particle-free solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Short duration analgesia during premedication, induction and maintenance of anaesthesia, and in the immediate post-operative period.
Opioid analgesic supplement to general and regional anaesthesia.
Combination with a neuroleptic as an anaesthetic premedication for the induction of anaesthesia, and as an adjunct in the maintenance of general and regional anaesthesia.

4.2 Dose and Method of Administration

Dosage should be individualised according to age, bodyweight, physical status, underlying pathological condition, use of other drugs, type of anaesthesia to be used and the surgical procedure involved (see Section 4.4 Special Warnings and Precautions for Use). Fentanyl Juno contains no antimicrobial agent. It should be used only once and any residue discarded.
Vital signs should be monitored routinely.

Adults.

Premedication. (To be appropriately modified in the elderly, debilitated and those who receive other depressant drugs): 50 to 100 microgram (1 to 2 mL) may be administered intramuscularly 30 to 60 minutes prior to surgery.
Adjunct to general anaesthesia.

Induction.

50 to 100 microgram (1 to 2 mL) IV initially, repeat at two to three minute intervals until desired effect is achieved. A reduced dose of 25 to 50 microgram (0.5 to 1 mL) is recommended in elderly and poor risk patients.

Maintenance.

25 to 50 microgram (0.5 to 1 mL) IV or IM when movement and/or changes in vital signs indicate surgical stress or lightening of analgesia.
Adjunct to regional anaesthesia. 50 to 100 microgram (1 to 2 mL) may be administered IM or slowly IV when additional analgesia is required.
Postoperatively (recovery room). 50 to 100 microgram (1 to 2 mL) may be administered IM for the control of pain, tachypnoea and emergence delirium. The dose may be repeated in one or two hours as needed.

Children.

For induction and maintenance in children 2 to 12 years of age, a reduced dose of 20 to 30 microgram (0.4 to 0.6 mL) per 10 kg is recommended.

Renal impairment.

Fentanyl should be used with caution.

Hepatic impairment.

Fentanyl should be used with caution.

Instructions for use and handling.

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 Special Warnings and Precautions for Use, Respiratory depression (hypoventilation)).
Wear gloves while opening the 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.

4.3 Contraindications

Known hypersensitivity or intolerance to fentanyl, any of the components of Fentanyl Juno or other opioid. Fentanyl should not be administered to patients suffering from bronchial asthma.
As for any opioid analgesic, fentanyl should not be used in patients with severe respiratory disease, acute respiratory disease and those susceptible to respiratory depression, such as comatose patients who may have head injuries or brain tumour (see Section 4.4 Special Warnings and Precautions for Use).

Concomitant MAO inhibitors.

Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. There is no evidence that fentanyl is potentiated by MAO inhibitors, but since such potentiation is found with other opioid analgesics, the use of fentanyl in patients who have received MAO inhibitors within 14 days is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Myasthenia gravis.

Fentanyl may cause muscle rigidity upon IV administration. Therefore, the need for reversal with muscle relaxants contraindicates its use in patients with a history of myasthenia gravis.
Children two years of age or younger. Safe conditions for use have not been established.
Use in patients after operative interventions in the biliary tract.
Use in chronic (long-term) non-cancer pain.

4.4 Special Warnings and Precautions for Use

Adequate facilities should be available for post-operative monitoring and ventilation.
Resuscitative equipment, oxygen and an opioid antagonist should be readily available to manage apnoea.
Fentanyl should only be used by experienced doctors and in patients who are under constant supervision.

Hazardous and harmful use.

Fentanyl Juno contains the opioid fentanyl and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed fentanyl at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed fentanyl.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Abuse or intentional misuse of fentanyl may result in overdose and/or death. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Fentanyl Juno with anyone else.

Respiratory depression (hypoventilation).

Depression of respiration is the most marked and dangerous side effect of fentanyl. In the post-operative period, patients may exhibit delayed depression of respiration. Hyperventilation during anesthesia may alter the patient's response to CO2, thus affecting respiration postoperatively. Patients should be monitored for this possibility and appropriate countermeasures taken as necessary.
Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of fentanyl, but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma, patients with decreased respiratory reserve, or any patient with potentially compromised respiration), and in patients with renal or hepatic disease (see Use in hepatic impairment and Use in renal impairment). In such patients, opioids may further decrease respiratory drive and increase airway resistance. Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). During anaesthesia, this risk can be managed by assisted or controlled respiration. The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids (see Section 4.2 Dose and Method of Administration). Consider starting the new opioid at a reduced dose to account for individual variation in response.
Respiratory depression caused by opioid analgesics is dose related and can be reversed by opioid antagonists, such as naloxone, but additional doses of naloxone may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist. Consult individual prescribing information (naloxone) before employing opioid antagonists. Appropriate surveillance should be maintained because the duration of respiratory depression of doses of fentanyl employed during anaesthesia may be longer than the duration of opioid antagonist action. The use of an opioid antagonist will also reverse analgesia. Also see Section 4.9 Overdose for discussion of opioid antagonists.
Respiratory depression is more likely to occur with intravenous administration if a dose is given too rapidly and it rarely occurs with intramuscular administration.
Resuscitative equipment and an opioid antagonist should be readily available to manage apnoea.
Opioids can cause central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.
The effect on respiratory depression persists longer than the measured analgesic effect, and care should be taken, with the total opioid dose considered when fentanyl is given postoperatively. The recommended dose may be as low as quarter of that normally prescribed.

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of fentanyl with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe fentanyl concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while being treated with fentanyl.

Tolerance and opioid use disorder (abuse and dependence).

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid. Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses to achieve an adequate therapeutic effect.
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).
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate. Abrupt withdrawal of fentanyl in those physically dependent may precipitate withdrawal syndrome, including convulsions.
When discontinuing fentanyl in a person who may be physically dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Neonatal withdrawal syndrome.

There is a risk that newborn infants will experience neonatal withdrawal syndrome following prolonged use of opioids, including fentanyl, during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Fentanyl Juno, especially by children, can result in a fatal overdose of fentanyl. Patients and their caregivers should be given information on safe storage and disposal of unused Fentanyl Juno (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance and opioid use disorder (abuse and dependence)). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance and opioid use disorder (abuse and dependence)). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Other.

Concomitant neuroleptics.

If fentanyl is administered with neuroleptics, the user should be familiar with the special properties of each drug, particularly with regard to durations of action. In addition, when such a combination is used, fluids and other countermeasures to manage hypotension should be available.

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 reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake 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.

Total opioid dose.

As with other potent opioids, the respiratory depressant effect of fentanyl persists longer than the measured analgesic effect. The total dose of all opioid analgesics should be considered before additional opioid analgesics are given during recovery from anaesthesia. It is recommended that post-operative opioids, when required, should be used initially in reduced doses, as low as 1/4 to 1/3 of those usually recommended.

Muscle rigidity.

Fentanyl may cause muscle rigidity, particularly involving the muscles of respiration. This effect is related to the dose and speed of injection and may be reduced by slow intravenous injection. If this effect occurs, it may be managed by the use of assisted or controlled respiration and, if necessary, by administration of a neuromuscular blocking agent compatible with the patient's condition.
Nonepileptic (myo)clonic movements can occur.

Head injuries and increased intracranial pressure.

Fentanyl is contraindicated in patients who may be particularly susceptible to respiratory depression, such as comatose patients who may have a head injury or brain tumour (see Section 4.3 Contraindications). In addition, fentanyl may obscure the clinical course of patients with a head injury.
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 short-lasting reduction of the cerebral perfusion pressure.

Cardiac effects.

Fentanyl may produce bradycardia, and possibly cardiac arrest if the patient has received an insufficient amount of anticholinergic, or when fentanyl is combined with non-vagolytic muscle relaxants. Bradycardia may be treated with atropine; however, fentanyl should be used with caution in patients with cardiac bradyarrhythmias.
Opioids may induce hypotension, particularly in hypovolaemic patients. Appropriate measures should be taken to maintain stable arterial pressure.

Sphincter of Oddi spasm.

As has been observed with all opioid analgesics, episodes suggestive of sphincter of Oddi spasm may occur with fentanyl.

Obese patients.

Fentanyl should be administered with additional caution in obese patients. Obese patients should be observed carefully for signs of fentanyl toxicity.

Fentanyl as a supplement for anaesthesia.

Certain forms of conduction anaesthesia, such as spinal anaesthesia and some peridural anaesthetics, can alter respiration by blocking intercostal nerves.
Through other mechanisms fentanyl can also alter respiration. Therefore, when fentanyl is used to supplement these forms of anaesthesia, the anaesthetist should be familiar with the physiological alterations involved and be prepared to manage them in patients selected for these forms of anaesthesia.

Monitoring.

Vital signs should be monitored routinely.

Use in hepatic impairment.

Fentanyl should be administered with caution to patients with liver dysfunction because of the importance of this organ in the metabolism and excretion of drugs.

Use in renal impairment.

Opioids should be titrated with caution. It is recommended to reduce the dosage of fentanyl in patients with renal impairment. They should be observed carefully for signs of fentanyl toxicity. Such patients also require prolonged post-operative monitoring.

Use in the elderly and debilitated patients.

The initial fentanyl dose should be reduced in elderly and debilitated patients. Elderly patients may be more susceptible to adverse effects, such as respiratory depression and cardiovascular effects. They may also have age related kidney function impairment, resulting in lower clearance rates of fentanyl. Opioids should be titrated with caution in patients with any of the following conditions: uncontrolled hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism, impaired hepatic or renal function. Such patients also require prolonged postoperative monitoring.

Paediatric use.

The safety of fentanyl in children younger than two years of age has not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Other CNS depressants.

Other CNS depressant drugs, e.g. barbiturates, tranquilizers, benzodiazepines or related drugs, alcohol, neuroleptics, opioids, general anaesthetics, gabapentinoids (gabapentin and pregabalin), cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines and centrally-active anti-emetics will have additive or potentiating effects with fentanyl.
When patients have received such drugs, the dose of fentanyl required will be less than usual. Concomitant use of fentanyl in spontaneous breathing patients may increase the risk of respiratory depression, profound sedation, coma and death (see Section 4.4 Special Warnings and Precautions for Use). Post-operative opioids including fentanyl and other depressants should be given initially in reduced doses, as low as 1/4 to 1/3 of those usually recommended. As with other opioids, the respiratory depressant effect of fentanyl persists longer than the measured analgesic effect. The total dose of all opioid analgesics should be considered before ordering opioid analgesics during recovery from anaesthesia.

Effect of fentanyl on other medicines.

Following the administration of fentanyl the dose of other CNS depressant drugs should be reduced (see Section 4.4 Special Warnings and Precautions for Use). 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 benzodiazepine or related drugs, during this period may disproportionally increase the risk of respiratory depression (see Section 4.4 Special Warnings and Precautions for Use).
For etomidate, the total plasma clearance is decreased by 2.7-fold and volume of distribution is decreased by a factor 2.4 while half-life increased by 1.2 times 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.

Conduction anaesthesia.

Certain forms of conduction anaesthesia, such as spinal anaesthesia and some peridural anaesthetics, can alter respiration by blocking intercostal nerves. Through other mechanisms (see Section 5 Pharmacological Properties) fentanyl can also alter respiration. Therefore, when fentanyl is used to supplement these forms of anaesthesia, the anaesthetist should be familiar with the special properties of each drug (particularly with the widely differing durations of actions), the physiological alterations involved and be prepared to manage them in patients selected for these forms of anaesthesia.

Fentanyl/neuroleptic combination (see Section 4.8 Adverse Effects (Undesirable Effects)).

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 a neuroleptic such as droperidol is used with fentanyl, pulmonary arterial pressure may be decreased. Hypotension can occur and, possibly, hypovolaemia (which should be managed with appropriate parenteral fluids).
Repositioning of the patient to improve venous return to the heart should be considered when operative conditions permit. Care should be exercised in moving and positioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids together with other countermeasures do not correct hypotension, the administration of pressor agents other than adrenaline should be considered. Because of the α-adrenergic blocking action of droperidol, adrenaline may paradoxically decrease the blood pressure in patients treated with droperidol. Pulmonary arterial pressure may also be decreased. This should be considered when interpreting pulmonary arterial pressure measurements as it might determine the final management of the patient. When droperidol is used with fentanyl and the EEG is used for postoperative monitoring, it may be found that the EEG pattern returns to normal slowly. Neuroleptics can induce extrapyramidal symptoms that can be controlled with antiparkinson agents.

MAO inhibitors.

Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Since the safety of fentanyl in this regard has not been established, the use of fentanyl in patients who have received monoamine oxidase inhibitors within 14 days is not recommended (see Section 4.3 Contraindications).

Lidocaine.

Concurrent administration of lidocaine and fentanyl may lead to a reduced seizure threshold.

Nitrous oxide.

Nitrous oxide has been reported to produce cardiovascular depression when given with high doses of fentanyl.

Amiodarone.

Profound bradycardia, sinus arrest and hypotension have occurred when patients receiving amiodarone have been given fentanyl for anaesthesia.

Adrenergic blockers and calcium channel blockers.

The combination of calcium channel blockers and beta-adrenergic blockers during fentanyl anaesthesia should be used with caution since severe hypotension has been reported to occur.

Serotonin syndrome.

Opioids can interact with antidepressants (such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) or monoamine oxidase inhibitor (MAOIs)) and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the brain and cause toxicity. See Section 4.4 Special Warnings and Precautions for Use.
Coadministration of sibutramine hydrochloride with fentanyl may increase the risk of serotonin syndrome (hypertension, hypothermia, myoclonus and mental status changes).

Cytochrome P450 3A4 (CYP 3A4) inhibitors.

Fentanyl, a high clearance drug, is rapidly and extensively metabolised in the liver via CYP 3A4 enzyme and has a high hepatic extraction ratio. Therefore, hepatic blood flow rather than enzyme activity is the main determinant of fentanyl clearance. Theoretically, co administration of CYP 3A4 enzyme inhibitors should cause only a small increase in plasma concentrations of fentanyl. When fentanyl is used, the concomitant use of a CYP3A4 inhibitor may result in a decrease in fentanyl clearance. With single-dose fentanyl administration, the period of a risk of respiratory depression may be prolonged, which may require special patient care and longer observation. With multiple-dose fentanyl administration, the risk for acute and/or delayed respiratory depression may be increased, and a dose reduction of fentanyl may be required to avoid accumulation of fentanyl.

Coadministration of the following drugs may enhance or prolong the effects of fentanyl.

Azole antifungals, macrolide antibiotics and protease inhibitors such as ritonavir.
Ritonavir is a highly potent inhibitor of CYP 3A4. Oral administration of ritonavir in healthy volunteers, at 200-300 mg t.d.s. for 2 days, significantly inhibits the metabolism of fentanyl at a dose of 5 microgram/kg, given as a single intravenous infusion over 2 minutes. Ritonavir decreased the clearance of fentanyl by 67%, prolonged the half-life of fentanyl by 100% and increased AUC (0 to infinity) by 174%. Ritonavir had no significant effect on the steady state volume of distribution of fentanyl. When fentanyl is given continuously with ritonavir, the dose of fentanyl should be reduced in order to lower the risk for severe and prolonged respiratory depression. When fentanyl is given as a single dose concomitantly with ritonavir, the duration of respiratory monitoring should be increased and the dose of fentanyl may need to be reduced.
Oral administration of itraconazole (another potent inhibitor of CYP 3A4) at 200 mg/day for 4 days did not have a statistically significant effect on the pharmacokinetics of fentanyl at a dose of 3 microgram/kg given as a single intravenous infusion over 2 minutes. Co-administration of other potent or less potent CYP3A inhibitors, such as voriconazole or fluconazole, and fentanyl may also result in an increased and/or prolonged exposure to fentanyl.
There are no data on the in vivo interactions between fentanyl and other drugs inhibiting CYP 3A4 (e.g. ketoconazole, erythromycin, diltiazem and cimetidine).

Coadministration of the following drugs may decrease the plasma concentration of fentanyl.

Phenytoin.

Other.

The concurrent administration of fentanyl and naltrexone precipitates opioid withdrawal symptoms.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Impairment of fertility has been observed in female rats given fentanyl 160 microgram/kg/day subcutaneously (no effect dose not established) or 400 microgram/kg/day intravenously (no effect dose 100 microgram/kg/day). Fertility in male rats was unaffected at 400 microgram/kg/day intravenously.
(Category C)
There are no adequate data from the use of fentanyl in pregnant women. The foetal respiratory centre is particularly sensitive to opiates. Intramuscular or intravenous administration during childbirth (including caesarean section) is not recommended because fentanyl crosses the placenta (foetal blood concentrations about 40% of maternal blood concentrations) 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. Prolonged use of an opioid, including fentanyl, during pregnancy may cause drug dependence in the neonate, leading to neonatal withdrawal syndrome. 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.
In pregnant rats, fentanyl is embryocidal as evidenced by increased resorptions at doses of 30 microgram/kg/day intravenously or 160 microgram/kg/day or greater subcutaneously. Intravenous administration to rats at 30 microgram/kg/day during organogenesis was associated with prolonged delivery time and increased postnatal mortality of offspring. There was no effect on embryofoetal development when rats received subcutaneous fentanyl at doses up to 500 microgram/kg/day throughout gestation, and no evidence of teratogenicity in rabbits administered fentanyl at intravenous doses up to 400 microgram/kg/day during organogenesis. The potential risk for humans is unknown.
 Fentanyl may enter the maternal milk and may cause sedation/respiratory depression in the newborn/infant. Therefore, breastfeeding or use of expressed breast milk is not recommended for 24 hours following the administration of this drug. The risk/benefit of breastfeeding following fentanyl administration should be considered.

4.7 Effects on Ability to Drive and Use Machines

Fentanyl may impair the mental and/or physical ability required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients must be cautioned accordingly. Patients should only drive or operate a machine if sufficient time has elapsed (at least 24 hours) after the administration of fentanyl.

4.8 Adverse Effects (Undesirable Effects)

More common.

Respiratory depression, apnoea, muscular rigidity, myoclonic movements and bradycardia, tachycardia, vein pain, dermatitis allergic.
If these remain untreated, respiratory arrest, circulatory depression, or cardiac arrest could occur.
Respiratory depression is more likely to occur with intravenous administration if a dose is given too rapidly; it rarely occurs with intramuscular administration. If respiratory depression occurs during anaesthesia, assisted or controlled respiration will provide adequate ventilation without reversing analgesia. Respiratory depression can be immediately reversed by opioid antagonists (e.g. nalorphine) which, it should be noted, will also reverse analgesia. Secondary rebound respiratory depression has been observed after the operation in rare instances.
Muscular rigidity may be associated with reduced pulmonary compliance and/or apnoea, laryngospasm or bronchospasm. Prompt reversal of this effect can be achieved with the intravenous administration of an appropriate single dose of a muscle relaxant such as suxamethonium. Assisted or controlled respiration is required to provide ventilation after the use of muscle relaxants.
Bradycardia and other cholinergic effects may occur and can be controlled with the appropriate dose of atropine. The inclusion of atropine or other anticholinergic agents in the pre-anaesthetic regimen tends to reduce the occurrence of such effects.

Less common.

Hypotension, hypertension, dizziness, blurred vision, miosis, nausea, emesis, laryngospasm, diaphoresis, itching, euphoria, seizures, spasm of the sphincter of Oddi, anaphylaxis, headache, loss of consciousness, myoclonus, phlebitis, hyperventilation, hiccups, hypothermia, airway complications of anaesthesia, agitation postoperative. Motor stimulation and bronchospasm may occur with high doses of fentanyl. Less frequently, cardiac arrhythmias, postoperative mental depression, paradoxical CNS excitation or delirium may occur.

Clinical trial data.

The safety of fentanyl was evaluated in 376 subjects who participated in 20 clinical trials evaluating fentanyl used as an anaesthetic. These subjects were administered at least one dose of fentanyl and provided safety data. Adverse drug reactions (ADRs), as identified by the investigator, reported for ≥ 1% of fentanyl-treated subjects in these studies are shown in Table 1.
Additional ADRs that occurred in < 1% of fentanyl injection-treated subjects in the 20 clinical trials are listed in Table 2.

Post-marketing data.

Adverse drug reactions first identified during post-marketing experience with fentanyl injection are included in Table 3, based on spontaneous reporting rates. The frequencies are provided according to the following convention: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1,000 and < 1/100; rare: ≥ 1/10,000, < 1/1,000; very rare: < 1/10,000, including isolated reports.

Fentanyl/neuroleptic combination.

When a neuroleptic such as droperidol is used with fentanyl, the following adverse reactions can occur: chills and/or shivering, restlessness and postoperative hallucinatory episodes sometimes associated with transient periods of mental depression; extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with antiparkinson agents.
Postoperative drowsiness is also frequently reported following the use of droperidol.
Elevated blood pressure with or without pre-existing hypertension, has been reported following administration of fentanyl combined with droperidol. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anaesthetic and surgical stimulation during light anaesthesia.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
The oral LD50 for fentanyl in rats is 18.0 mg/kg. The intravenous LD50 is 2.3 mg/kg, and the intramuscular LD50 is 1.0 mg/kg in rats. The toxic dose in man is unknown.

Signs and symptoms.

The manifestations of fentanyl overdosage are an extension of its pharmacological actions. In sufficient overdosage, fentanyl would produce narcosis which may be preceded by marked skeletal muscle rigidity. Respiratory depression, which can vary in severity from bradyapnoea to apnoea, may occur. This may be accompanied by cyanosis, followed by a fall in body temperature, circulatory collapse, coma and death. Toxic leukoencephalopathy has been observed with fentanyl overdose.

Treatment.

In the presence of hypoventilation or apnoea, oxygen should be administered and respiration assisted or controlled as necessary. A patent airway must be maintained.
If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular blocking agent might be required to facilitate assisted or controlled respiration.
A specific opioid antagonist, such as nalorphine or naloxone, should be available for use as indicated to manage respiratory depression. This does not preclude the use of more immediate countermeasures. The duration of respiratory depression following overdosage of fentanyl is usually longer than the duration of opioid antagonist action. The patient should be carefully observed for 24 hours. Body warmth and adequate fluid intake should be maintained. If hypotension occurs, and is severe or persists, the possibility of hypovolaemia should be considered and managed with appropriate parenteral fluid therapy. The use of an opioid antagonist will also reverse analgesia.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fentanyl is an opioid analgesic. A dose of 100 microgram (0.1 mg or 2.0 mL) is approximately equivalent in analgesic activity to 10 mg of morphine or 75 mg of pethidine. The principal actions of therapeutic value are analgesia and sedation. Alterations in respiratory rate and alveolar ventilation associated with opioid analgesics may last longer than the analgesic effect. As the dose of opioid is increased, the decrease in pulmonary exchange becomes greater. Large doses may produce apnoea. Fentanyl appears to have less emetic activity than either morphine or pethidine. Histamine assays and skin wheal testing in man indicate that clinically significant histamine release rarely occurs with fentanyl. Recent assays in man show no clinically significant histamine release at doses up to 50 microgram/kg (0.05 mg/kg or 1 mL/kg). Fentanyl preserves cardiac stability and blunts stress-related hormonal changes at higher doses.
Fentanyl produces minimal cortical depression and may act by filling receptor sites located in the thalamus, midbrain and spinal cord. A specific morphine antagonist (e.g. nalorphine) produces reversal of respiratory, cardiovascular, miotic and motor incoordination effects and also produces reversal of analgesia, euphoria and sedation. Rigidity of the diaphragm and intercostal muscles can be eliminated by suxamethonium. Cholinergic effects such as bradycardia are reversed by atropine.
As with longer-acting opioid analgesics, the duration of the respiratory depressant effect of fentanyl may be longer than the analgesic effect. The following observations have been reported concerning altered respiratory response to CO2 stimulation following administration of fentanyl to man:
1. Diminished sensitivity to CO2 stimulation may persist longer than depression of respiratory rate. Fentanyl frequently slows the respiratory rate, but this effect is seldom noted for longer than 30 minutes regardless of the dose administered (see Section 4.4 Special Warnings and Precautions for Use).
2. Altered sensitivity to CO2 stimulation has been demonstrated for up to four hours following a single intravenous dose of 600 microgram (12 mL) fentanyl to healthy volunteers.
3. Duration and degree of respiratory depression is dose related.
4. The peak respiratory depressant effect of a single intravenous dose of fentanyl is noted 5 to 15 minutes following injection. (See Section 4.4 Special Warnings and Precautions for Use concerning respiratory depression).

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption and distribution.

The pharmacokinetics of fentanyl can be described by a three-compartment model, with a distribution time of 1.7 minutes, redistribution of 13 minutes and a terminal elimination half-life of 219 minutes. The volume of distribution for fentanyl is 4 L/kg.
The onset of action is almost immediate when the drug is given intravenously; however, the maximal analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is 30 to 60 minutes after a single IV dose of up to 100 microgram. Following intramuscular administration, the onset of action is from seven to eight minutes and the duration of action is one to two hours.
Fentanyl plasma protein binding capacity increases with increasing ionisation of the drug.
Alterations in pH may affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat, and is released slowly into the blood.

Metabolism and excretion.

Fentanyl is primarily transformed in the liver and demonstrates a high first pass clearance with approximately 75% of an intravenous dose excreted in urine, primarily as metabolites with less than 10% representing the unchanged drug. Approximately 9% of the dose is recovered in the faeces, primarily as metabolites. Fentanyl has a terminal elimination half-life of 219 minutes.

Special populations.

Paediatrics.

Pharmacokinetic information in children is limited and obtained from different sources. CYP3A4 activity is very low at birth but increases after birth to reach 30-40% of adult levels at 1 month of age. The clearance and volume of distribution adjusted for body weight are higher in infants and children than in adults after IV administration of fentanyl. The terminal elimination half-life is longer in newborn infants. See Table 4.
After intravenous administration, the plasma protein binding of fentanyl in newborn infants is lower than in adults. It is higher in preterm neonates (77%) than in those born at term (approximately 62%).

Adult patients with burns.

An increase in median clearance of 45% together with a larger volume of distribution results in lower fentanyl plasma concentrations. This may require an increased dose of fentanyl.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, water for injections, sodium hydroxide for pH adjustment.

6.2 Incompatibilities

Fentanyl is incompatible with thiopental sodium and methohexitone sodium.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

2 mL or 10 mL clear Type I glass ampoules in packs of 10.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

990-73-8.
Fentanyl citrate is chemically identified as N-(1-phenethyl-4-piperidyl) propionanilide citrate, MW: 528.61. The chemical formula is C22H28N2O.C6H8O7.

7 Medicine Schedule (Poisons Standard)

Controlled drug (Schedule 8).

Summary Table of Changes