Consumer medicine information

Fentanyl Sandoz

Fentanyl

BRAND INFORMATION

Brand name

Fentanyl Sandoz

Active ingredient

Fentanyl

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fentanyl Sandoz.

SUMMARY CMI

Fentanyl Sandoz®

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 using Fentanyl Sandoz?

Fentanyl Sandoz contains the active ingredient fentanyl. Fentanyl Sandoz is used for the long-term management of severe pain that requires daily around-the-clock pain relievers, when other treatment options are not able to effectively manage your pain, or you cannot tolerate them. Fentanyl Sandoz is only used in people who have previously been using other opioid-based pain relief.

For more information, see Section 1. Why am I using Fentanyl Sandoz? in the full CMI.

2. What should I know before I use Fentanyl Sandoz?

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 I use Fentanyl Sandoz? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fentanyl Sandoz 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 do I use Fentanyl Sandoz?

  • Fentanyl Sandoz is available in five different patches, each with a different size and strength. Your doctor will decide which patch, or combination of patches, is suitable to control your pain. The lowest effective strength should be used.

More instructions can be found in Section 4. How do I use Fentanyl Sandoz? in the full CMI.

5. What should I know while using Fentanyl Sandoz?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Fentanyl Sandoz.
  • Always follow your doctor's instructions carefully. Accidental exposure or improper use including Fentanyl Sandoz patches sticking to another person can be life-threatening.
  • Tell your doctor if you develop a fever.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not expose the patch to direct heat. Direct exposure to such heat may cause an increase in the amount of fentanyl absorbed by the skin, resulting in possible overdose and death.
Driving or using machines
  • Fentanyl Sandoz can affect your alertness and ability to drive and operate machinery. Be careful before you drive or use any machines or tools until you know how Fentanyl Sandoz affects you.
Drinking alcohol
  • You must not drink alcohol while using Fentanyl Sandoz. Their combined effect may cause severe drowsiness, decreased awareness, breathing problems, coma and death.
Looking after your medicine
  • Keep Fentanyl Sandoz patches in the sealed pouch until it is time to apply them.
  • Keep the patches in a dry place where temperature stays below 25°C.
  • Store this medicine securely, where other people cannot access it. It may harm people who may take this medicine by accident, or intentionally.

For more information, see Section 5. What should I know while using Fentanyl Sandoz? in the full CMI.

6. Are there any side effects?

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

Life threatening respiratory depression

Fentanyl Sandoz can cause life-threatening or fatal breathing difficulties (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 Sandoz 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.

Concomitant use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol

Using Fentanyl Sandoz 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 Sandoz.



FULL CMI

Fentanyl Sandoz®

Active ingredient(s): fentanyl

Consumer Medicine Information (CMI)

This leaflet provides important information about using Fentanyl Sandoz. 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 Sandoz.

Where to find information in this leaflet:

1. Why am I using Fentanyl Sandoz?
2. What should I know before I use Fentanyl Sandoz?
3. What if I am taking other medicines?
4. How do I use Fentanyl Sandoz?
5. What should I know while using Fentanyl Sandoz?
6. Are there any side effects?
7. Product details

1. Why am I using Fentanyl Sandoz?

Fentanyl Sandoz contains the active ingredient fentanyl. Fentanyl Sandoz is an opioid analgesic which are a group of strong pain relievers. Fentanyl relieves pain by blocking the nerves that recognise pain messages from the body.

Fentanyl Sandoz is used for the long-term management of pain that is severe enough to require daily around-the-clock pain relievers, when other treatment options are not able to effectively manage your pain or you cannot tolerate them. Fentanyl Sandoz is only used in people who have previously been using other opioid-based pain relief. Fentanyl Sandoz is not used to treat pain that you only have once in a while.

Each patch is applied onto the skin every three days (72 hours). The patch releases a continuous amount of fentanyl that is absorbed through the skin in contact with the patch.

2. What should I know before I use Fentanyl Sandoz?

Warnings

Opioids can be abused and misused, and you are at risk for opioid addiction, even if you take your dose as prescribed. Opioid addiction, abuse and misuse can lead to overdose and death.

Fentanyl Sandoz may become habit-forming causing mental and physical dependence. If abused, it may become less able to reduce pain.

Fentanyl Sandoz patches may be retrieved and abused or misused illegally. Please ensure that used patches are concealed and disposed of carefully. Return unused patches to the pharmacy (see Getting rid of any unwanted medicine at the end of this leaflet).

Keep used and unused patches where children cannot reach them. A patch may be tempting to a child. Accidental exposure or ingestion of used or unused Fentanyl Sandoz patches, particularly in children, may result in breathing difficulties, with slow or shallow breathing, that could lead to death. Improper use including Fentanyl Sandoz patches sticking to another person can be life-threatening.

Fentanyl Sandoz can cause sleep apnoea (stopping breathing from time to time while sleeping) which can lead to low levels of oxygen in the blood. Tell your doctor if you have a history of sleep apnoea or if anyone notices you stop breathing from time to time whilst sleeping.

Opioids can cause a high level of the hormone 'prolactin' and low levels of sex hormones in the blood. The effects of these hormone changes may include:

  • In females – unexpected production of breast milk; loss of menstrual periods
  • In males – enlarged breasts; difficulty getting and keeping an erection (impotence)
  • In females or males – decreased sex drive; infertility.

Tell your doctor if you notice any of these symptoms. You may need blood tests, and your doctor may tell you to stop using Fentanyl Sandoz.

Opioids can cause a decreased level of hormones in the blood caused by a problem with the adrenal glands. The effects of these hormone changes may include:

  • Nausea, vomiting, loss of appetite, feeling very tired and weak, feeling dizzy, or low blood pressure.

Tell your doctor if you notice any of these symptoms. You may need blood tests, and your doctor may tell you to stop using Fentanyl Sandoz.

Tolerance

As with all opioid analgesics, Fentanyl Sandoz may lead to tolerance with continued use. Tolerance means that the effect of the medicine may decrease and more is needed to produce the same effect. Therefore, it is possible your doctor will prescribe a higher dose of Fentanyl Sandoz after some time to produce the same result.

Dependence and withdrawal

As with all other opioids, your body may become used to you taking Fentanyl Sandoz after several days to weeks of continued use resulting in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking Fentanyl Sandoz suddenly. Some examples of withdrawal symptoms include feeling uneasy and unwell, restless, agitated, anxious, increased pain, sweating, chills, weakness, stomach cramps, problems sleeping, nausea, vomiting, diarrhoea, increased blood pressure, fast breathing and fast heartbeat.

Fentanyl Sandoz must be stopped by decreasing the dose gradually. Your doctor will tell you how to do this, and will regularly monitor and support any increase in pain or withdrawal symptoms.

Increased sensitivity to pain

Rarely, increasing the dose of this medicine can make you more sensitive to pain. If this happens, you need to speak to your doctor about your treatment.

Do not use Fentanyl Sandoz:

  • If you are allergic to fentanyl, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • for acute pain or pain following surgery
  • for mild or intermittent pain
  • at a starting dose greater than 25 micrograms/hour
  • if you have any lung condition or breathing difficulties
  • if you have not used any opioid analgesics in the past.
    This is because you may be more likely to experience some of the side effects.

Do not use Fentanyl Sandoz if the packaging is torn or shows signs of tampering.

Do not use Fentanyl Sandoz beyond the expiry date (month and year) printed on the pack.

Check with your doctor if you:

  • have any other medical conditions, particularly:
    - have or have ever had problems with your liver or kidney
    - have or have ever had problems with your lungs or breathing difficulties
    - have sleep apnoea or if anyone notices you stop breathing from time to time while sleeping
    - have or have ever had problems with your heart
    - have or have ever had a brain tumour or head injuries
    - have problems with your stomach or intestines such as bowel blockage
    - have problems with your immune system or medical conditions which lower your resistance to diseases.
  • take any medicines for any other condition
  • (or a family member) have ever abused or been dependent on alcohol, prescription medicines, or illegal drugs or have a mental illness. Your doctor will advise you whether or not to use Fentanyl Sandoz or if you need to adjust the dose or adapt your treatment.

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.

Your doctor will decide whether you may use Fentanyl Sandoz if you are pregnant or plan to become pregnant.

Fentanyl Sandoz should not be used during childbirth as the medicine can slow the breathing of the newborn child. Prolonged use of Fentanyl Sandoz during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognised and treated.

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

If you are breast feeding, you should not use Fentanyl Sandoz since it may be present in your milk. See your doctor.

Use in children and adolescents

Fentanyl Sandoz should not be used in children under 12 years of age or in adolescents under 18 years of age who weigh less than 50 kg.

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 Sandoz and affect how it works.

In particular, tell your doctor or pharmacist if you are taking any of the following:

  • medicines that slow down your central nervous system, for example:
    - medicines that makes you sleepy, reduce anxiety such as sedatives, hypnotics, sleeping tablets, tranquillisers (benzodiazepines)
    - other opioid medicines
    - medicines used for surgery (anesthetics) and muscle relaxants
    - antihistamines or allergy medicine that makes you drowsy
    - gabapentinoid medicines used to treat epilepsy or nerve pain such as gabapentin and pregabalin
    - alcohol, cannabis or some illegal drugs.
    Taking these medicines with Fentanyl Sandoz may make you even more drowsy, slow down your ability to react, have decrease awareness, breathing difficulties with slow or shallow breathing, coma and death.

A change in dose by your doctor may be required if Fentanyl Sandoz is used with these medicines:

  • antidepressant medicines belonging to the class monoamine oxidase inhibitors (MAOIs).
    Fentanyl Sandoz should not be used together with MAOIs as this may cause severe serotonin syndrome which is a potentially life-threatening condition. Signs and symptoms can include confusion, restlessness, fever, heavy sweating, fast or irregular heart rate, diarrhoea, uncoordinated movement of limbs or eyes, uncontrollable jerking of muscles, seizures and unconsciousness. Do not use Fentanyl Sandoz if you have taken a MAOI in the last 14 days.
  • other antidepressant medicines belonging to the class selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants (TCAs) and nefazodone. Combination of these medicines with Fentanyl Sandoz may increase the risk of serotonin syndrome.
  • medicines used to treat mental illness or psychotic conditions and to relieve severe nausea and vomiting, such as phenothiazines.
  • certain antibiotics used to treat infections such as erythromycin, clarithromycin and troleandomycin.
  • certain medicines to treat fungal infections such as fluconazole, ketoconazole, itraconazole and voriconazole.
  • ritonavir and nelfinavir (used to treat AIDS).
    Do not take ritonavir or nelfinavir while using Fentanyl Sandoz, unless you are closely monitored by your doctor.
  • if taking rifampicin, carbamazepine, phenobarbital or phenytoin, careful monitoring by your doctor and dose adjustment may be required.
  • idelalisib (cancer treatment)
  • certain medicines that act on the heart and blood vessels such as calcium-channel blockers like verapamil and diltiazem, nicardipine.
  • certain medicines used to treat arrhythmias such as amiodarone.

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 Sandoz.

4. How do I use Fentanyl Sandoz?

How much to use

  • Fentanyl Sandoz is available in five different patches, each with a different size and strength. Your doctor will decide which patch, or combination of patches, is suitable to control your pain. The lowest effective strength should be used.

Using it for the first time

  • The first patch may take up to a day to take effect after it is applied onto the skin. This is because fentanyl is slowly absorbed through the skin into the blood. Your doctor may prescribe additional medicines to control the pain for the first day.

Applying the patch

  1. Find an intact and hairless spot of skin on the upper part of your body or on your upper arm. Do not place the patch onto skin that is red, burnt or damaged.
The skin should be healthy and undamaged.
  1. Trim any excess hair with scissors. Do not shave the hair off since this may affect the skin. If you need to wash the skin before applying the patch, use clean water only. Do not use soap, oils or lotions.
The skin should be completely dry before applying the patch.
  1. Open the pouch and remove the Fentanyl Sandoz patch. Do not apply the patch if it looks damaged in any way. Never cut or divide the patch.
  2. Remove the protective film.
    Avoid touching the adhesive side of the patch.
  3. Apply the patch to the skin and press with the palm of the hand for about 30 seconds. Make sure all of the patch is in contact with skin and the corners are stuck tightly.
  4. Wash your hands after applying or removing the patch.

You can now leave the patch on the skin for three days (72 hours).

You may have a bath, shower or swim.

Always write the date and time you applied the patch on the pack.

It will help you to use Fentanyl Sandoz correctly and remember when the next patch is due.

Changing the patch

  1. After three days (72 hours), remove the patch.
  2. Fold the used patch in half so that the adhesive side sticks to itself. Wrap the folded patch and carefully dispose of it in the garbage.
  3. Apply a new patch straight away to a different area of the skin, following the steps under 'Applying the patch'.

If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

If your pain continues, see your doctor who may prescribe additional medicines to help control the pain or change the dose of Fentanyl Sandoz. Your doctor may advise you initially to change the patch every two days (48 hours) instead of every three days (72 hours) to achieve adequate pain relief.

How to long to use Fentanyl Sandoz

  • Continue using your medicine for as long as your doctor tells you.

If you forget to use Fentanyl Sandoz

If you forget to apply a patch, and are not sure what to do, check with your doctor or pharmacist.

If you have trouble remembering when to apply each patch, ask your pharmacist for some hints.

If you use too much Fentanyl Sandoz

If you think that you have used too much Fentanyl Sandoz, you may need urgent medical attention.

You should immediately remove the patch(es) and phone triple zero (000) in Australia or triple one (111) in New Zealand for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then.

Also,

  • phone the Australian Poisons Information Centre
    (by calling 13 11 26), or the New Zealand National Poisons Information Centre (by calling 0800 POISONS or 0800 764766), or
  • go to the Emergency Department at your nearest hospital.

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

Symptoms of an overdose with Fentanyl Sandoz may include:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heart beat
  • Nausea or vomiting
  • Convulsions or fits

Other signs of overdose can also include problems with the 'nervous system' caused by damage to the white matter of the brain (known as toxic leukoencephalopathy).

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

5. What should I know while using Fentanyl Sandoz?

Things you should do

  • Always follow your doctor's instructions carefully.
  • If you are pregnant or plan to become pregnant, you should inform your doctor, who will decide whether you may use Fentanyl Sandoz.
  • If your pain continues or returns, see your doctor. You may need additional medicines to control the pain or a change in the strength of the Fentanyl Sandoz patch.
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are using Fentanyl Sandoz.

Call your doctor straight away if you:

  • develop a fever. At high temperatures, the amount of fentanyl absorbed by the skin increases. Your doctor may need to adjust your Fentanyl Sandoz dose.

Remind any doctor, dentist or pharmacist you visit that you are using Fentanyl Sandoz.

Things you should not do

  • Do not stop using this medicine suddenly unless your doctor advises you to do so. If you have been using Fentanyl Sandoz for a long period of time but stop using it suddenly without your doctor's advice, you may experience withdrawal symptoms such as:
    - trouble sleeping, nervousness, restlessness, agitation 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
    Seek your doctor's advice if you experience these symptoms.
  • DO NOT expose the patch to direct heat from electric blankets, heat pads, heated water beds, heat or tanning lamps, intensive sunbathing, hot water bottles, long hot baths, saunas or hot spa baths while you are using Fentanyl Sandoz. Direct exposure to such heat may cause an increase in the amount of fentanyl absorbed by the skin, resulting in possible overdose and death.
  • Do not cut, break, chew, crush, dissolve, snort or inject Fentanyl Sandoz. This can result in serious side effects and death.
  • Do not change your dose without first checking with your doctor
  • Do not give the patches to anyone else, even if their symptoms seem similar to yours as they could die from taking it.

Things to be careful of

  • If the patch accidentally sticks to another person (for example a family member sharing the same bed) or is accidentally swallowed (for example by a child),
  • remove the patch and phone triple zero (000) in Australia or triple one (111) in New Zealand. Do this even if there are no signs of discomfort or drowsiness.
  • Different brands of fentanyl patches may vary in size, shape, colour or adhesiveness.
  • DO NOT switch brands of fentanyl patches unless your doctor and pharmacist authorise it.

Driving or using machines

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

Fentanyl Sandoz can affect your alertness and ability to drive and operate machinery. Do not drive or operate machinery until you know how this medicine affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

You must not drink alcohol while using Fentanyl Sandoz since their combined effect may cause severe drowsiness, decreased awareness, breathing problems, coma and death.

Looking after your medicine

  • Keep the patches in a dry place where temperature stays below 25°C.
  • Store this medicine securely, where other people cannot access it. It may harm people who may take this medicine by accident, or intentionally when it has not been prescribed for them.
  • Keep Fentanyl Sandoz patches in the sealed pouch until it is time to apply them.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, 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.

Getting rid of any unwanted medicine

The contents of Fentanyl Sandoz patches may be retrieved and abused or misused illegally.

Fold used patches so that the adhesive side of the patch sticks to itself, then wrap and dispose of it carefully.

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

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.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal-related:
  • nausea, vomiting, constipation, dry mouth, diarrhoea, uncomfortable feeling in stomach or belching after eating, indigestion, blockage in the bowel, problem with the movement of food or drink through the food pipe.
Blood pressure-related:
  • low blood pressure, headache, weakness or dizziness, high blood pressure, being less alert or aware, or loss of consciousness.
  • blurred vision
Sleep-related:
  • sleepiness, confusion, hallucinations, euphoria, depression, loss of appetite, anxiety, trouble sleeping, agitation, loss of memory, pins and needles.
  • stopping breathing from time to time whilst sleeping (sleep apnoea).
Skin-related:
  • skin rash (local redness and itch at the site of the patch is usually mild and resolves when the patch is removed).
  • thinning or redness where the patch has been on the skin; ulcer (sore) where the patch has been on the skin.
Other:
  • unusual tiredness or weakness, feeling of body temperature change; swelling of the feet, ankles and hands.
  • nausea, vomiting, diarrhoea, anxiety and shivering may occur initially when you are switched from other opioid analgesics to Fentanyl Sandoz or if therapy is stopped suddenly.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Heart-related:
  • slow heartbeat
  • fast heartbeat
Breathing-related:
  • breathing slows or weakens
  • temporarily stopped breathing
  • difficulty in breathing
The risk of breathing problems is higher if you:
  • have an existing lung condition
  • have a small physique
  • are an elderly patient
  • have kidney or liver disease
  • are given a high Fentanyl Sandoz dose
  • you have not used opioid pain relief before.
Nervous system-related:
  • numbness; seizures or fits.
  • involuntary muscle movements including muscle spasms.
  • sweating or trouble urinating
Allergy-related:
  • sudden life-threatening allergic reaction.
Symptoms may include:
  • rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.
REMOVE the Fentanyl Sandoz patch and phone triple zero (000) in Australia or triple one (111) in New Zealand or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Make sure that you are with someone who can keep you awake by talking to you or gently shaking you every now and then.

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.

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 or to Medsafe at pophealth.my.site.com/carmreportnz/s/. 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 Sandoz contains

Active ingredient
(main ingredient)		fentanyl
Other ingredients
(inactive ingredients)		polyethylene terephthalate
acrylic-vinylacetate copolymer
siliconised polyethylene terephthalate

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

What Fentanyl Sandoz looks like

Fentanyl Sandoz patches are transparent rounded oblong patches. They are individually packed in sachets and are available in packs containing 5 sachets.

  • Fentanyl Sandoz 12 mcg/h - 12 microgram fentanyl released per hour (AUST R 152572)
  • Fentanyl Sandoz 25 mcg/h - 25 microgram fentanyl released per hour (AUST R 152569)
  • Fentanyl Sandoz 50 mcg/h - 50 microgram fentanyl released per hour (AUST R 152571)
  • Fentanyl Sandoz 75 mcg/h - 75 microgram fentanyl released per hour (AUST R 152568)
  • Fentanyl Sandoz 100 mcg/h - 100 microgram fentanyl released per hour (AUST R 152576)

Who distributes Fentanyl Sandoz

Fentanyl Sandoz is distributed in Australia by:

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

Fentanyl Sandoz is distributed in New Zealand by:

Sandoz New Zealand Limited
12 Madden Street
Auckland 1010
New Zealand
Tel: 0800 726 369

This leaflet was prepared in February 2025.

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS April 2025

BRAND INFORMATION

Brand name

Fentanyl Sandoz

Active ingredient

Fentanyl

Schedule

S8

 

1 Name of Medicine

Fentanyl.

2 Qualitative and Quantitative Composition

It is available in six different strengths delivering fentanyl 12, 25, 37, 50, 75 or 100 microgram/hour to the systemic circulation. The amount of fentanyl released from each patch per hour is proportional to the surface area. The composition per unit area of all patches is identical.
* The lowest dose is designated as 12 microgram/hour (however, the actual dosage is 12.5 microgram/hour) to distinguish it from a 125 microgram/hour dosage that could be prescribed by using multiple patches.
** Actual dosage is 37.5 microgram/hour.
Fentanyl Sandoz 12* microgram/h transdermal patch - surface area of 5.25 cm2.
Fentanyl Sandoz 25 microgram/h transdermal patch - surface area of 10.5 cm2.
Fentanyl Sandoz 37** microgram/h transdermal patch - surface area of 15.75 cm2.
Fentanyl Sandoz 50 microgram/h transdermal patch - surface area of 21 cm2.
Fentanyl Sandoz 75 microgram/h transdermal patch - surface area of 31.5 cm2.
Fentanyl Sandoz 100 microgram/h transdermal patch - surface area of 42 cm2.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fentanyl Sandoz is a fentanyl matrix transdermal drug delivery system (patch).
Fentanyl Sandoz is a transparent rounded oblong unit comprising a protective liner and two functional layers.
Before use, the protective liner covering the adhesive layer is removed and discarded.

4 Clinical Particulars

4.1 Therapeutic Indications

For the management of pain associated with cancer, palliative care, and other conditions in patients where:
other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain; and
the pain is opioid-responsive; and
severe enough to require daily, continuous, long term opioid treatment.
Not for use in opioid-naive patients.

4.2 Dose and Method of Administration

Dosage.

With all opioids, the safety of patients using the products is dependent on health care practitioners prescribing them in strict conformity with their approved labelling with respect to patient selection, dosing and proper conditions for use (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Fentanyl doses should be individualised based on the status of the patient and should be assessed at regular intervals after application. Bodyweight, clearance and respiratory function should be considered in selection of initial doses (see Section 4.4 Special Warnings and Precautions for Use).
Initial dose selection. The appropriate initiating dose of fentanyl should be based on the patient's current opioid use. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. It is recommended that fentanyl be used in patients who have demonstrated opioid tolerance. Other factors to be considered are the current general condition and medical status of the patient including body size, age and extent of debilitation as well as degree of opioid tolerance.
Opioid tolerant patients. To convert opioid tolerant patients from oral or parenteral opioids to fentanyl patches, refer to equianalgesic potency conversion (Table 1) and recommended fentanyl dose based on daily oral morphine dose (Table 2). The dosage may subsequently be titrated upwards or downwards, if required, in increments of either 12 or 25 microgram/hour to achieve the lowest appropriate dose of fentanyl depending on response and supplementary analgesic requirements.

Equianalgesic potency conversion.

To convert from oral or parenteral opioids to fentanyl patches, the following procedures should be followed.
1. Calculate the previous 24-hour analgesic requirement.
2. Convert this amount to the equianalgesic oral morphine dose using Table 1. All intramuscular and oral doses in this chart are considered equivalent to 10 mg of intramuscular morphine in analgesic effect. Table 1 should not be used to convert from fentanyl patches to other therapies because this conversion to fentanyl patches is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible.
3. Table 2 and Table 3 displays the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl dose. Use this table to derive the fentanyl dose from the calculated 24-hour morphine dose.
4. Table 2 is for adult patients who have a need for rotation of, or conversion from, another opioid regimen (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 150:1).
5. Table 3 is for adult patients with cancer pain who are on a stable, and well-tolerated opioid regimen (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 100:1).
The initial evaluation of the maximum analgesic effect of fentanyl should not be made before the patch has been worn for 24 hours. This is due to the gradual increase in serum fentanyl concentration in the 24 hours following initial application of the patch. Previous analgesic therapy should therefore be phased out gradually after the initial dose application until the analgesic efficacy with fentanyl is attained.
Dose titration and maintenance therapy. Each fentanyl patch should be replaced every 72 hours. The dose should be titrated individually until adequate analgesic efficacy and tolerability is attained. If analgesia is insufficient dosage adjustment can occur every three days after the initial application. Early in therapy, some patients may not achieve adequate analgesia during the third day using this dosing interval and may require fentanyl patch to be applied at 48 hours rather than 72 hours. Reducing the duration of patch application by replacing the patch before the 72 hours may result in increased serum concentrations of fentanyl (see Section 5.2 Pharmacokinetic Properties).
A 12 microgram/hour strength is available which equates to oral morphine approximately 45 mg/day. The 12 microgram/hour strength is particularly useful for titration at lower dosages.
Dosage titration should normally be performed in 12 or 25 microgram/hour increments, although the supplementary analgesic requirements (oral morphine 45/90 mg/day is approximately equivalent to fentanyl 12/25 microgram/hour) and pain status of the patient should be taken into account. More than one fentanyl patch may be used for doses greater than 100 microgram/hour. Patients may require periodic supplemental doses of a short acting analgesic for 'breakthrough' pain. Some patients may require additional or alternative methods of opioid administration when the fentanyl dose exceeds 300 microgram/hour.

Discontinuation of therapy.

As fentanyl levels decrease gradually after the fentanyl patch is removed, replacement with other opioids should be gradual, starting at a low dose and increasing slowly. After system removal, serum fentanyl concentrations decline gradually with mean terminal half-life ranging from 22 to 25 hours. In general, discontinuation of any opioid analgesia should be gradual in order to prevent withdrawal symptoms. There have been reports that rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms and uncontrolled pain (see Section 4.4 Special Warnings and Precautions for Use, Ceasing opioids). Opioid withdrawal symptoms are possible in some patients after conversion or dose adjustment (see Section 4.8 Adverse Effects (Undesirable Effects)).
Table 2 and Table 3 should not be used to convert from fentanyl patches to other therapies to avoid overestimating the new analgesic dose and potentially causing overdose. Use of multiple patches carries an increased risk of medication errors which has the potential for serious outcome.

Method of administration.

Fentanyl patches should not be cut nor divided. Damaged patches should not be used (see Section 4.4 Special Warnings and Precautions for Use).
Fentanyl patches should be applied immediately upon removal from the sealed package. The patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges.
Carers should be advised to avoid contact with the adhesive when applying the patch to the patient.
Each fentanyl patch should be worn continuously for 72 hours. A new patch should be applied to a different skin site after removal of the previous patch. Several days should elapse before a new patch is applied to the same area of the skin.

Instructions to the patient.

Fentanyl should be kept out of reach of children before, during and after use.
Fentanyl can impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving or operating machinery.
Only one patch of fentanyl should be worn at a time unless there is a specific need otherwise (for example to obtain a dose that cannot be achieved with a single patch). Patients should be instructed to remove the old patch before the new patch is applied.

Application site.

Fentanyl should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arms. Hair at the application site (a non-hairy area is preferable) should be clipped (not shaved) prior to application. If the site of fentanyl application requires cleansing prior to application of the patch, this should be done with clean water. Soaps, oils and lotions, or any other agent that might irritate the skin or alter its characteristics, should not be used. The skin should be completely dry before the patch is applied. Patches should be inspected prior to use. Patches that are cut, divided, or damaged in any way should not be used (see Section 4.2 Dose and Method of Administration).
In a study to assess the phototoxicity effect after patch removal, the results showed that 24 and 48 hours after irradiation, the incidence of erythema at the patch site was slightly higher (87% and 65%) than the unpatched site (62% and 51%) and all reactions were mild in nature. Nevertheless, patients should be advised to cover the application site after removal of the patch if going out in the sun or avoid baking altogether.

Instructions for use/handling.

Fentanyl should be applied immediately upon removal from the sealed package. First locate the pre-cut notch (indicated by scissors on the patch label) along the edge of the seal, the pouch should be folded at the notch, and then carefully torn. The pouch should then be further opened along both sides, folding it open like a book. Then the patch should be removed from the protective liner. The release liner is slit. After folding the patch in the middle, each half of the liner should be separately removed. Patients should avoid touching the adhesive side of the patch. The patch must be applied to the skin by applying light pressure with the palm of the hand for about 30 seconds, making certain the edges are adhering properly.
Patients should wash hands afterwards with clean water.

External heat sources.

All patients should be advised to avoid exposing the fentanyl application site to heat sources such as heating pads, electric blankets, heated water beds, heat or tanning lamps, intensive sunbathing, hot water bottles, prolonged hot baths, saunas and hot spa-baths whilst wearing the patch. Exposure to heat could result in a temperature dependant increase in fentanyl release from the patch (see Section 4.4 Special Warnings and Precautions for Use, Effect of fever/external heat).

Accidental adhesion to another person.

The patch must only be used by the person for whom it was prescribed. A few cases are known where a patch has accidentally adhered to another family member sharing the same bed as the patient. Patients should be advised that in case of adhesion to the skin of another person, the patch must be taken off immediately and a doctor called (see Section 4.9 Overdose).

Safe disposal of the patches.

The contents of fentanyl patches may be retrieved and used accidentally (for example by children) or deliberately (for example by people with substance use disorders). Therefore, used patches must be disposed of carefully. Fold used patches so that the adhesive side of the patch adheres to itself, wrap and dispose of carefully. Unused patches should be returned to the pharmacy (see Section 6.6 Special Precautions for Disposal). Keep used patches out of sight and reach of children - even used patches contain some medicine which may harm children and may even be fatal.

4.3 Contraindications

Fentanyl Sandoz is contraindicated in patients with known hypersensitivity to fentanyl or to the adhesives present in the patch.
Fentanyl Sandoz should not be used in the following circumstances because serious or life threatening hypoventilation may occur and can be fatal:
the management of acute or postoperative pain since there is no opportunity for dose titration during short-term use; and
in the management of mild or intermittent pain that can be managed by non-opioid analgesics or 'as required' dosing with short acting opioids; and
at doses exceeding 25 microgram/hour at the initiation of opioid therapy because of the need to individualise dosing by titrating to the desired analgesic effect.
Severe respiratory disease, acute respiratory disease and respiratory depression.

4.4 Special Warnings and Precautions for Use

Patients who have experienced serious adverse events should be monitored for at least 24 hours after removal of fentanyl patches, or more as clinical symptoms dictate, since serum fentanyl concentrations decline gradually with mean terminal half-life ranging from 22 to 25 hours.
Fentanyl patches should not be cut or divided. Damaged patches should not be used. The patch should not be cut. A patch that has been divided, cut, or damaged in any way should not be used.
The contents of disposed patches may be retrieved and ingested or injected by addicts. Deaths have occurred as a result of such abuse. Please ensure that used patches are concealed and disposed of carefully (see Section 4.2 Dose and Method of Administration, Method of administration, Instructions to the patient; Section 6.6 Special Precautions for Disposal).
The initial fentanyl dose should be the lowest possible dose based on the patient's opioid history and the current medical status. Dosage must be titrated upward as required (see Section 4.2 Dose and Method of Administration).
Fentanyl patches are not recommended in opioid naive patients. This is due to a high incidence of adverse events in these patients (see Section 4.8 Adverse Effects (Undesirable Effects)).
Opioid use disorder can result in some cases from the prescription of opioids.

Switching between different brands.

Different brands of fentanyl patches may vary in size, shape, colour or adhesive characteristics. To avoid patient confusion, switching brands of fentanyl patches should only occur under guidance of the treating physician and dispensing pharmacist.

Opioid naive and not opioid tolerant states.

Use of fentanyl transdermal system in the opioid naive patient has been associated with very rare cases of significant respiratory depression and/or fatality when used as initial opioid therapy. The potential for serious or life threatening hypoventilation exists even if the lowest dose of fentanyl transdermal system is used in initiating therapy in opioid naive patients, especially in elderly or patients with hepatic or renal impairment. The tendency of tolerance development varies widely among individuals. It is recommended that fentanyl patches be used in patients who have demonstrated opioid tolerance (see Section 4.2 Dose and Method of Administration, Initial dose selection). It is not recommended for use in opioid-naive patients.

Hazardous and harmful use.

Fentanyl Sandoz contains the opioid fentanyl and is a potential drug of abuse, misuse and addiction. Fentanyl can be abused in a manner similar to other opioids. Abuse or intentional misuse of fentanyl patches may result in overdose and/or death. 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 addition prior to being prescribed fentanyl.
All patients receiving opioids should be routinely monitored for signs or misuse and abuse. 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 Sandoz with anyone else.

Respiratory depression.

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. Respiratory depression may persist beyond the removal of the fentanyl patch.
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) and in patients with hepatic and renal impairment (see subsections Use in hepatic impairment and Use in renal impairment of this section). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications). Risk factors for developing respiratory depression include small habitus and decreased clearance of fentanyl due to hepatic or renal impairment.
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 naive 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 (see Section 4.2 Dose and Method of Administration), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
CNS active drugs may increase the risk of developing respiratory depression (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Opioids can cause sleep-related breathing disorders such as sleep apnoea syndrome (including central sleep apnoea [CSA]) and hypoxia (including sleep-related hypoxia) (see Section 4.8 Adverse Effects (Undesirable Effects)). Opioid use increases the risk of CSA in a dose-dependent fashion. Evaluate patients on an ongoing basis for the onset of a new sleep apnoea, or a worsening of an existing sleep apnoea. In these patients, consider reducing or stopping the opioid treatment if appropriate, using best practices for tapering of opioids (see Section 4.2 Dose and Method of Administration, Discontinuation of therapy).

Chronic pulmonary disease.

Fentanyl patches may have more severe adverse effects in patients with chronic obstructive or other pulmonary disease. In such patients, opioids may decrease respiratory drive and increase airway resistance.

Central nervous system conditions including increased intracranial pressure.

Fentanyl patches should be used with caution in patients who are particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness or coma. Fentanyl patches should be used with caution in patients with brain tumours.

Cardiac disease.

Opioids may induce hypotension, especially in hypovolaemic patients. Measures may need to be taken to maintain a stable arterial pressure. Fentanyl can produce bradycardia and should therefore be administered with caution to patients with bradyarrhythmias.

Impaired immunity.

Patients with compromised immune function should be closely monitored for skin reactions when treated with fentanyl patches as local irritation may result in severe skin infections in such individuals.

Effect of fever/external heat.

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C, resulting in possible overdose and death. This is due to temperature dependent increases in fentanyl release from the patch and increased skin permeability. Thus, patients wearing fentanyl patches who develop fever should be monitored for opioid side effects and the dose should be adjusted if necessary. All patients should be advised to avoid exposing the fentanyl patch to direct external heat sources (see Section 4.2 Dose and Method of Administration, Method of administration, Instructions to the patient).

Accidental ingestion/exposure.

Accidental ingestion or exposure of fentanyl, especially by children, can result in a fatal overdose of fentanyl. Accidental transfer of a fentanyl patch to the skin of non-patch wearer (particularly a child), while sharing a bed or being in close physical contact with a patch wearer, may result in an opioid overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs, the transferred patch must be removed immediately from the skin of the non-patch wearer (see Section 4.9 Overdose). Patients and their caregivers should be given information on safe storage and disposal of unused fentanyl (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

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 taking fentanyl (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Alcohol.

Use of fentanyl in combination with alcoholic beverages and/or other CNS depressants can result in increased risk to the patient. Fentanyl patches should be used with caution in individuals who have a history of drug or alcohol abuse, especially if they are outside a medically controlled environment.

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid naive patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptor 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.
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.
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 and see Section 4.2 Dose and Method of Administration).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Opioid induced hyperalgesia is a paradoxical response to an opioid in which there is an increase in pain perception despite stable or increased opioid exposure. 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 or pain from ordinary (i.e. non-painful) stimuli (allodynia) with no evidence of disease progression. Hyperalgesia should not be confused with tolerance. It differs from tolerance, in which higher opioid doses are required to achieve the same analgesic effect or treat recurring pain (see Tolerance, dependence and withdrawal). 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.

Hyperprolactinemia.

Long term opioid use may be associated with increased prolactin levels and decreased sex hormone levels. Symptoms may include galactorrhea, gynecomastia, impotence, decreased libido, infertility, or amenorrhea. If hyperprolactinemia is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Fentanyl Sandoz should be considered.

Adrenal insufficiency.

Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Fentanyl Sandoz should be considered.

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, dependence and withdrawal). 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 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.

Gastrointestinal tract.

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Patients should be advised on measures to prevent constipation and prophylactic laxative use should be considered. Extra caution should be used in patients with chronic constipation. If paralytic ileus is present or suspected, treatment with fentanyl patch should be stopped.

Concomitant use of mixed agonists/antagonists.

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. (Also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

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] (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). This may occur within the recommended dose.
Serotonin syndrome may include mental-status changes (e.g. agitation, hallucination, 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, treatment with fentanyl should be discontinued.

Patients with myasthenia gravis.

Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.

Use in hepatic impairment.

As fentanyl is metabolised to inactive metabolites in the liver, hepatic disease might delay its elimination. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of fentanyl reduced if necessary (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Less than 10% of fentanyl is excreted unchanged by the kidney and, unlike morphine, there are no known active metabolites eliminated by the kidney. If patients with renal impairment receive fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary. Even though impairment of renal function is not expected to affect fentanyl elimination to a clinical relevant extent, caution is advised because fentanyl pharmacokinetics has not been evaluated in this patient population (see Section 5.2 Pharmacokinetic Properties).
Treatment should only be considered if the benefits outweigh the risks.

Use in the elderly.

Data from intravenous studies with fentanyl suggest that in elderly patients there may be a reduced clearance and prolonged half-life. Elderly patients may, therefore, be more sensitive to the drug than younger patients.
Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 5.2 Pharmacokinetic Properties).
Since elderly, cachectic or debilitated patients may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance, they should not be started on doses greater than 25 microgram/hour unless they have previously been taking another opioid equivalent to at least 135 mg of oral morphine a day (see Section 4.2 Dose and Method of Administration).

Paediatric use.

The safety and efficacy of fentanyl patch in children have not been established.
Until further experience is gained, fentanyl patches should not be administered to children under 12 years of age or patients under 18 years of age who weigh less than 50 kg, except in an authorised investigational setting.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Central nervous system (CNS) depressants, including alcohol and some illegal drugs.

The concomitant use of fentanyl with other central nervous system depressants, including benzodiazepines and other sedative/hypnotics, opioids, general anaesthetics, phenothiazines, tranquillizers, skeletal muscle relaxants, monoamine oxidase inhibitors, sedating antihistamines and alcohol and some illegal drugs may disproportionately increase the CNS depressant effects. Respiratory depression, hypotension and profound sedation, coma or death may occur. Therefore, the use of any of these drugs concomitantly with fentanyl patches requires special patient care and observation. Dose reduction of one or both medicinal products should be taken into consideration (also see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Monoamine oxidase inhibitors (MAOI).

Fentanyl patches are not recommended for use in patients who require the concomitant administration of an MAOI (e.g. linezolid, phenelzine, tranylcypromine). Severe and unpredictable interactions with MAOIs, involving the potentiation of opiate effects or the potentiation of serotonergic effects, have been reported. Since the safety of fentanyl in this regard has not been established, the use of fentanyl in patients who have received MAOIs in the previous 14 days is not recommended.

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), tricyclic antidepressants (TCA), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g. mirtazapine, trazodone, tramadol) or a monoamine oxidase inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition. Use concomitantly with caution. Carefully observe the patient, particularly during treatment initiation and dose adjustment (see Section 4.4 Special Warnings and Precautions for Use).

Cytochrome P450 3A4 (CYP3A4) inhibitors.

Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly via human cytochrome P450 3A4 (CYP3A4) enzyme.
The concomitant use of fentanyl with CYP3A4 inhibitors (e.g. erythromycin, fluconazole, idelalisib, nicardipine, ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, troleandomycin, voriconazole, verapamil, diltiazem and amiodarone) may result in an increase in fentanyl plasma concentrations which could increase or prolong both the therapeutic and adverse effects and may cause serious respiratory depression. Cases of serious respiratory depression after coadministration of CYP3A4 inhibitors with transdermal fentanyl have been reported, including a fatal case after coadministration with a moderate CYP3A4 inhibitor. The extent of interaction with strong CYP3A4 inhibitors is expected to be greater than with weak or moderate CYP3A4 inhibitors. Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of intravenous fentanyl by two thirds, whereas oral administration of itraconazole (a less potent inhibitor of CYP3A4) at 200 mg/day given orally for four days did not have a statistically significant effect on the pharmacokinetics of intravenous fentanyl. In this situation, special patient care and observation are appropriate. Therefore, the concomitant use of transdermal fentanyl and CYP3A4 inhibitors is not recommended unless the benefits outweigh the increased risk of adverse effects.
Generally, a patient should wait for at least 2 days after stopping treatment with a CYP3A4 inhibitor before applying the first fentanyl patch. More time is needed for CYP3A4 inhibitors with a long half-life (such as amiodarone), or CYP3A4 inhibitors with time-dependent or mechanism-based inhibition (such as erythromycin, nicardipine, idelalisib and ritonavir). The product information of the CYP3A4 inhibitor must be consulted for the active substance's half-life and duration of the inhibitory effect before applying the first fentanyl patch.
A patient who is treated with fentanyl should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor. If concomitant use of fentanyl with a CYP3A4 inhibitor cannot be avoided, close monitoring signs or symptoms of increased prolonged therapeutic effects and adverse of effects of fentanyl (in particular respiratory depression) is warranted, and the fentanyl dosage must be reduced or interrupted as deemed necessary.

Cytochrome P450 3A4 (CYP3A4) inducers.

The concomitant use of fentanyl with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin) could result in a decrease in fentanyl plasma concentrations and a decreased therapeutic effect. This may require a dose adjustment of transdermal fentanyl. After stopping the treatment of a CYP3A4 inducer, the effects of the inducer decline gradually and may result in a fentanyl plasma increase concentration, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. In this situation, careful monitoring and dose adjustment should be made if warranted.

Concomitant use of mixed agonists/antagonists.

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependent patients.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In humans, the prolonged use of opioid analgesics may result in sexual dysfunction, infertility or impairment of fertility in both sexes and menstrual disturbance in women. The impairment of fertility has been observed in female rats given fentanyl 0.16 mg/kg/day subcutaneously (SC) (no effect dose not established) or 0.4 mg/kg/day intravenously (IV) (no effect dose 0.1 mg/kg/day, associated with plasma fentanyl concentrations similar to or lower than those expected in humans using 10 mg fentanyl patches). No effect was observed on the fertility of male rats treated with intravenous fentanyl 0.4 mg/kg/day.
(Category C)
Fentanyl crosses the placenta in humans and has been found in foetal blood at concentrations about 40% of those found in maternal blood. The safe use of fentanyl in pregnant women has not been established with respect to possible adverse effects on foetal development.
Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl during pregnancy.
Use of fentanyl patches during childbirth is not recommended because fentanyl passes through the placenta and may cause respiratory depression in the newborn infant and because it should not be used in the management of acute or postoperative pain (see Section 4.3 Contraindications).
Intravenous administration of fentanyl 0.03 mg/kg/day to rats during organogenesis was associated with a prolonged delivery time and increased postnatal mortality of offspring *(no-effect dose 0.01 mg/kg/day), but there was no evidence of teratogenic activity or of adverse effects on the development of surviving offspring. *In rabbits, there was no evidence of teratogenicity following intravenous administration of fentanyl during organogenesis at doses up to 0.4 mg/kg/day, associated with peak plasma levels up to 7 times greater than those expected in humans during treatment with 100 microgram/hour fentanyl patches. The significance of these findings for potential human risk is unknown.
 Fentanyl is excreted into human milk and may cause sedation/respiratory depression in a breastfed infant. Therefore, fentanyl patches are not recommended for use in breastfeeding women.
Intravenous infusion of fentanyl to female rats from early gestation to weaning was associated with reduced early postnatal survival at a dose of 0.4 mg/kg/day; the no effect dose was 0.1 mg/kg/day, associated with plasma fentanyl concentrations similar to or lower than those expected in humans using 100 microgram/hour fentanyl patches. The significance of these findings for potential human risk is unknown.

4.7 Effects on Ability to Drive and Use Machines

Fentanyl can impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

The most serious adverse reaction, as with all potent opioids, is hypoventilation. Other opioid related adverse reactions include nausea, vomiting, constipation, hypotension, bradycardia, somnolence, headache, confusion, hallucinations, euphoria, pruritus, sweating and urinary retention.
Skin reactions such as rash, pustules, papules, erythema, oedema and itching have occasionally been reported. These reactions usually resolve within 24 hours of removal of the patch. However, patients with compromised immune function should be carefully monitored for skin reactions (see Section 4.4 Special Warnings and Precautions for Use).
Reactions such as nausea, vomiting, anorexia, diarrhoea, sweating, shivering, anxiety and depression are associated with opioid withdrawal syndrome in some patients after converting to fentanyl from their previous opioid or if therapy is stopped suddenly. Slow tapering of the dose may lessen the severity of withdrawal symptoms. These effects are usually resolved by the administration of a short acting opioid on an 'as required' basis (see Section 4.2 Dose and Method of Administration).

Clinical trials data.

The safety of fentanyl patches was evaluated in 216 subjects who participated in a multicentre, double blind, randomized, placebo controlled clinical trial (FEN-EMA-1) of fentanyl. These subjects took at least one dose of fentanyl and provided safety data. This trial examined patients over 40 years of age with moderate to severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement. Patients were treated for 6 weeks with fentanyl by titrating to adequate pain control starting from 25 microgram/hour to a maximum dose of 100 microgram/hour in 25 microgram/hour increments. Adverse drug reactions (ADRs) reported for ≥ 1% of fentanyl treated subjects and with an incidence greater than placebo treated subjects are shown in Table 4.
Adverse drug reactions not reported in Table 4 that were reported by ≥ 1% of fentanyl-treated subjects (N=1854) in 11 clinical trials of fentanyl used for the treatment of chronic malignant or nonmalignant pain (which includes trial FEN-EMA-1) are shown in Table 5. All subjects took at least one dose of fentanyl and provided safety data.
Adverse drug reactions reported by < 1% of fentanyl treated subjects (N=1854) in the above clinical trial dataset are shown in Table 6.

Postmarketing data.

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience involving all indications with fentanyl are presented below. The adverse drug reactions are ranked by frequency, using the following convention: Very common: greater than or equal to 1/10; common: greater than or equal to 1/100 to < 1/10; uncommon: greater than or equal to 1/1,000 to < 1/100; rare: greater than or equal to 1/10,000 to < 1/1,000; very rare: < 1/10,000, including isolated reports.
The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports and do not represent more precise estimates that might be obtained in clinical trials or epidemiological studies.

Immune system disorders.

Very rare: anaphylactic shock, anaphylactic reaction, anaphylactoid reaction.

Metabolism and nutrition disorders.

Very rare: anorexia.

Psychiatric disorders.

Very rare: depression, confusional state, hallucination, anxiety, euphoric mood, agitation, insomnia.

Nervous system disorders.

Very rare: convulsions (including clonic convulsions and grand mal convulsion), amnesia, somnolence, dizziness, headache, tremor, paraesthesia, *depressed level of consciousness, loss of consciousness, sleep apnoea syndrome.

*Eye disorders.

Rare: miosis. *Very rare: vision blurred.

Cardiac disorders.

Very rare: tachycardia, bradycardia, cyanosis.

Renal and urinary disorders.

Very rare: urinary retention.

Vascular disorders.

Very rare: hypotension, hypertension.

Respiratory, thoracic and mediastinal disorders.

Very rare: respiratory depression (including respiratory distress, apnoea and bradypnoea (see Section 4.9 Overdose)), hypoventilation, dyspnoea, hypoxia.

Gastrointestinal disorders.

Very rare: nausea, vomiting, constipation, diarrhoea, dyspepsia, dry mouth, ileus, oesophageal motility disorder (including dysphagia).

Skin and subcutaneous tissue disorders.

Very rare: rash, erythema, pruritus, increased sweating.

Reproductive system and breast disorders.

Very rare: sexual dysfunction, androgen deficiency.

General disorders and administration site conditions.

Very rare: drug withdrawal syndrome, asthenia, application site reaction, feeling of body temperature change* pyrexia, application site erosion, application site ulcer.
*Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety and shivering) are possible in some patients after conversion from their previous opioid analgesic to fentanyl patches or if therapy is stopped suddenly (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Tolerance, dependence and withdrawal).
As with other opioid analgesics, tolerance, physical dependence and psychological dependence can develop on repeated use of fentanyl (see Section 4.4 Special Warnings and Precautions for Use, Tolerance, dependence and withdrawal).
There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used fentanyl patches during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Deaths, mainly due to respiratory depression, have been reported with the use of fentanyl in opioid naive patients. This information is listed to serve as an alert for the doctor.

Reporting 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

The manifestations of fentanyl overdosage are an extension of its pharmacological actions, the most serious effect being respiratory depression. Toxic leukoencephalopathy has also been observed with fentanyl overdose.

Treatment.

For the management of respiratory depression, immediate countermeasures include removing the fentanyl patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone. Respiratory depression following an overdose may outlast the duration of action of an opioid antagonist like naloxone owing to its relatively short half-life of 30 to 81 minutes. Therefore, the interval between intravenous antagonist doses should be carefully chosen because of the possibility of renarcotisation after the patch is removed. Repeated administration or a continuous infusion of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and release of catecholamines.
Because of the observed variability in the clearance of fentanyl and the occasional appearance of multiple peaks in serum concentration, careful observation of the patient should continue for at least 24 hours after removal of the fentanyl patch.
If the clinical situation warrants, a patent airway should be established and maintained, possibly with an oropharyngeal airway or endotracheal tube. Oxygen should be administered and respiration assisted or controlled, as appropriate. Adequate body temperature and fluid intake should be maintained. If severe or persistent hypotension occurs, hypovolaemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

Fentanyl is an opioid analgesic, interacting predominantly with mu-opioid receptors. These mu-binding sites are discretely distributed in the human brain, spinal cord and other tissues.

5.1 Pharmacodynamic Properties

It is a drug in adhesive formulation designed to release fentanyl continuously for 72 hours after application to intact skin.

Mechanism of action.

In the clinical setting, fentanyl exerts its principal pharmacological effects on the central nervous system. Its primary therapeutic actions are analgesia and sedation. In addition, alterations in mood, euphoria and dysphoria commonly occur. Fentanyl depresses the respiratory centre, the cough reflex and constricts the pupils. Analgesic serum concentrations of fentanyl may cause nausea and vomiting by directly stimulating the chemoreceptor trigger zone.
The approximate analgesic potency ratio of transdermally administered fentanyl to parenteral morphine ranges from 1:20 to 1:30 in opioid naive patients with acute pain.
Minimum effective analgesic serum concentrations of fentanyl in opioid naive patients range from 0.3 to 1.5 nanograms/mL and are reached approximately six hours after application of the patch. Adverse reactions increase in frequency at serum concentrations above 2.0 nanograms/mL.
Both the minimum effective concentration and the concentration at which opioid related adverse reactions occur rise with increasing patient tolerance to fentanyl. The rate of development of tolerance varies widely among individuals.
At equivalent analgesic serum concentrations, fentanyl and morphine produce a similar degree of hypoventilation. A small number of patients have experienced clinically significant hypoventilation with fentanyl. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mmHg. Episodes of slow respiration may occur at any time during therapy despite most patients developing tolerance to fentanyl induced hypoventilation with long-term use.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations. The risk of hypoventilation increases at serum fentanyl concentrations greater than 2.0 nanograms/mL in opioid naive patients, especially for patients who have an underlying pulmonary condition or who concurrently receive the usual analgesic doses of other opioids or CNS drugs associated with hypoventilation.
At therapeutic doses, fentanyl does not exert major effects on the cardiovascular system. However, some patients may exhibit orthostatic hypotension and fainting.
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening of pain rather than relief.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.
Histamine assays and skin wheal testing in humans indicate that clinically significant histamine release rarely occurs with fentanyl administration. Assays in humans show no clinically significant histamine release at doses up to 50 microgram/kg.

Clinical trials.

Clinical trials were conducted in 542 cancer patients and 847 noncancer patients to evaluate the efficacy of fentanyl in the management of chronic pain. All trials were open labelled or nonrandomised with the exception of one randomised double blind trial in cancer patients (n = 88) and two open randomised, crossover trials in cancer (n = 93) and non-cancer (n = 251) patients, respectively. Fentanyl patches were applied at 72 hour intervals.
The results of these trials demonstrated that satisfactory analgesia was achieved when doses were titrated to effective levels. Patients also preferred fentanyl patches over their previous analgesic, such as oral sustained release morphine. The safety of fentanyl patches has been assessed in 871 cancer patients and 921 noncancer patients. Fentanyl was found to have a similar safety profile to other opioid drugs. Central nervous system and gastrointestinal adverse reactions were the most frequent reactions (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the chronic cancer pain trials, the doses of fentanyl patch varied between 25 and 600 microgram/hour to a maximum continued use of two years. Changes in the Visual Analogue Scale (VAS) pain scores ranged from a 10% increase (worse pain) to a greater than 50% decrease (less pain) with fentanyl compared to their previous opioid treatment. One controlled trial involving 88 patients showed no difference in pain control between fentanyl patch and placebo, however this result may be explained by the short duration of the trial (nine days).
In the chronic non-cancer pain trials, patients with neuropathic pain, AIDS related pain, lower back pain and other nociceptive pain were included. Short acting oral morphine was available to patients for breakthrough pain. The results show that fentanyl patch provides at least as good a level of pain control and quality of life as other analgesics, such as oral sustained release morphine.

5.2 Pharmacokinetic Properties

Absorption.

Fentanyl patches provide continuous systemic delivery of fentanyl during the 72 hour application period. The release of fentanyl from the patch is sufficiently controlled by the skin stratum corneum. While the actual rate of fentanyl delivery to the skin varies over the 72 hour application period, each patch is labelled as the average amount of fentanyl delivered to the systemic circulation per hour across average skin.
Despite variability in the dose of fentanyl delivered among patients, the average rate of delivery (12, 25, 37, 50, 75 or 100 microgram/hour) is sufficiently accurate to allow individual titration of dosage for a given patient.
Variations in skin temperature may affect the delivery rate of fentanyl due to changes in skin permeability. For example, fever may result in a more rapid delivery rate, while hypovolaemia or surgical cooling may result in a slower delivery rate (see Section 4.4 Special Warnings and Precautions for Use, Effect of fever/external heat).
After initial application of fentanyl patches, serum fentanyl concentrations increase gradually. The accumulation of fentanyl within skin tissue results in a significant delay before maximum serum concentrations are reached. Peak serum concentrations of fentanyl generally occur between 24 and 72 hours after the first application.
The serum fentanyl concentrations attained are proportional to the fentanyl patch size. After repeated 72 hour applications, serum concentration reaches a steady state that is maintained during subsequent applications of the same size patch (see Figure 1).
A pharmacokinetic model has suggested that serum fentanyl concentration may increase by 14% (range 0-26%) if a new patch is applied after 24 hours rather than the recommended 72 hour application.

Distribution.

The average volume of distribution for fentanyl is 6 L/kg (range 3 to 8 L/kg, n = 8). The plasma protein binding capacity of fentanyl decreases with increasing ionisation of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in skeletal muscle and fat and is then released slowly into the blood. Estimates of mean values for unbound fractions of fentanyl in plasma are between 13 and 21%. (See Table 7.)

Metabolism.

Fentanyl is a high clearance drug, and it is metabolised rapidly and primarily in the liver via the human cytochrome P450 3A4 (CYP 3A4) enzyme. In humans, it is metabolised primarily by N-dealkylation to norfentanyl and other inactive metabolites. The liver has a high intrinsic capacity to metabolise fentanyl. Clearance is therefore determined mainly by the rate at which the drug is presented to the liver, that is, by liver blood flow. Clinical trials indicate that the skin does not appear to metabolise fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation. The major metabolite, norfentanyl, is inactive.

Excretion.

The average clearance in patients undergoing various surgical procedures is 46 L/hour (range 25 to 75 L/hour, n = 8). Individuals vary in their capacity to clear fentanyl. Multiple peaks in serum concentration of fentanyl have been observed during fentanyl administration (see Figure 1).
Within 72 hours of IV fentanyl administration, approximately 75% of fentanyl is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of the dose is recovered in the faeces, primarily as metabolites.
After fentanyl patches are removed, serum fentanyl concentrations decline gradually, falling about 50% in about 17 (range 13-22) hours following a 24 hour application. Following a 72 hour application, the mean half-life ranges from 20-27 hours. Continued absorption of fentanyl from within the skin accounts for the slower clearance from the serum than is seen after administration of fentanyl by intravenous infusion.
Following application of a single fentanyl patch (25 microgram/hour) for 72 hours to healthy subjects after controlled fasting, a mean peak plasma concentration (Cmax) of fentanyl of approximately 633.0 picogram/mL was achieved after approximately 22 hours (Tmax).
Following consecutive application of three fentanyl patches (25 microgram/hour) for 72 hours each, a mean peak plasma concentration of fentanyl under steady state (Cmax,ss) of approximately 767.12 picogram/mL was achieved after approximately 16.59 hours (Tmax,ss).

Special populations.

Elderly.

Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the drug than younger patients. In a study conducted with fentanyl patch, healthy elderly subjects had fentanyl pharmacokinetics which did not differ significantly from healthy young subjects although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Fentanyl should be used with caution in elderly, cachectic or debilitated patients as they may have altered pharmacokinetics due to poor fat storage, muscle wasting, or altered clearance. If it is used in elderly patients, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

In a study conducted with patients with hepatic cirrhosis, the pharmacokinetics of a single 50 microgram/hour application of fentanyl patch were assessed. Although tmax and t1/2 were not altered, the mean plasma Cmax and AUC values increased by approximately 35% and 73%, respectively, in these patients. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of fentanyl reduced if necessary (see Section 4.4 Special Warnings and Precautions for Use).

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 patch, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Fentanyl and other components of the fentanyl patch showed no evidence of genotoxic potential in assays for gene mutations (Ames reverse mutation test and mouse lymphoma thymidine kinase assay), chromosomal damage (Chinese hamster ovary cells, mouse micronucleus test) and other genotoxic effects (unscheduled DNA synthesis in rat hepatocytes, cell transformation assay in Balb/c-3T3 cells).

Carcinogenicity.

In a two year study in rats, there was no evidence of carcinogenicity following daily subcutaneous administration of fentanyl at the maximum tolerated dose. Systemic exposures (plasma area under the concentration time curve (AUC)) were substantially below human therapeutic levels.

6 Pharmaceutical Particulars

6.1 List of Excipients

From the outer surface to the surface adhering to skin, these layers include the following: a backing of polyethylene terephthalate (PET) film, a drug in adhesive reservoir, which contains fentanyl and acrylic-vinylacetate copolymer; an oversized protective liner of siliconised PET.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.5 Nature and Contents of Container

The drug containing adhesive matrix of the transdermal patch is covered with a siliconised protective foil (release liner) which protects the adhesive side of the patch during all handling procedures.
The fentanyl transdermal patches are individually packed in sachets and are available in cartons containing 1*, 2*, 3*, 4*, 5, 7*, 8* or 10* sachets.
* Not currently marketed in Australia.

6.6 Special Precautions for Disposal

The contents of fentanyl patches may be retrieved and potentially abused. Fold used patches so that the adhesive side of the patch adheres to itself then wrap and dispose of carefully. Unused patches should be returned to the pharmacy. In medical institutions, the usual opioid disposal arrangements should be utilised.

6.7 Physicochemical Properties

Fentanyl is a derivative of 4-anilinopiperidine. Fentanyl is a white to off white solid which is slightly soluble in aqueous neutral and alkaline solutions but is readily soluble in acidic aqueous solutions and organic solvents. It has a pKa of 8.4 and a partition coefficient (n-octanol: aqueous buffer pH 11) log P of 3.94. Two polymorphic forms (I and II) have been identified for fentanyl, although polymorphic form II spontaneously converts to polymorphic form I.

Chemical structure.


Chemical name: N-phenyl-N-[1- (2-phenylethyl)- 4-piperidinyl]propanamide.
Molecular formula: C22H28N2O.
Molecular weight: 336.5 g/mol.

CAS number.

437-38-7.

7 Medicine Schedule (Poisons Standard)

Schedule 8 - Controlled Drug.

Summary Table of Changes