Consumer medicine information

Durogesic

Fentanyl

BRAND INFORMATION

Brand name

Durogesic

Active ingredient

Fentanyl

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Durogesic.

What is in this leaflet

This leaflet answers some common questions about DUROGESIC patches. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using DUROGESIC against the benefits this medicine is expected to have for you.

If you have any concerns about using DUROGESIC, ask your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What DUROGESIC is used for

DUROGESIC 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. DUROGESIC is only used in people who have previously been using other opioid-based pain relief. DUROGESIC is not used to treat pain that you only have once in a while.

DUROGESIC patches contain a medicine called fentanyl. This strong pain reliever belongs to a group of medicines known as opioid analgesics. Fentanyl relieves pain by blocking the nerves that recognise pain messages from the body.

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.

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

Before you use DUROGESIC

Warning

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.

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

DUROGESIC 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 Disposal 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 DUROGESIC patches, particularly in children, may result in breathing difficulties, with slow or shallow breathing, that could lead to death. Improper use including DUROGESIC patches sticking to another person can be life-threatening.

DUROGESIC 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.

Tolerance

As with all opioid analgesics, DUROGESIC 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 DUROGESIC after some time to produce the same result.

Dependence and withdrawal

As with all other opioids, your body may become used to you taking DUROGESIC 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 DUROGESIC 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.

DUROGESIC 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.

When you must not use it

Do not use DUROGESIC

  • if you have an allergy to fentanyl or any of the ingredients. See Product Description at the end of this leaflet for a list of ingredients.
  • 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 DUROGESIC if the packaging is torn or shows signs of tampering. Do not use DUROGESIC beyond the expiry date (month and year) printed on the pack.

Before you start to use it

You must tell your doctor if you

  • are pregnant or planning to become pregnant
  • are breast feeding or wish to breastfeed
  • 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.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using or are given DUROGESIC.

Tell your doctor if you (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 DUROGESIC or if you need to adjust the dose or adapt your treatment.

Children

DUROGESIC 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.

Taking other medicines

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

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 DUROGESIC 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 DUROGESIC is used with these medicines.
  • antidepressant medicines belonging to the class monoamine oxidase inhibitors (MAOIs). DUROGESIC 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 DUROGESIC if you have taken an 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 DUROGESIC 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 DUROGESIC, 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

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

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

Using DUROGESIC

How to use the patch

Adults
DUROGESIC 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.

Using and changing the patches
Make a note of the day, date and time you apply a patch, to remind you when you need to change your patch.

There is enough medicine in each patch to last 3 days (72 hours).

You should change your patch every third day, unless your doctor has told you differently. If the patch comes off before 3 days, a new patch of the same strength should be applied to a new spot of intact skin.

Always remove the old patch before applying a new one.

Always change your patch at the same time of day every 3 days (72 hours).

You should not use more than one patch at a time, unless your doctor authorises otherwise (for example to obtain a dose that cannot be achieved with a single patch). If you are using more than one patch, change all your patches at the same time.

The old patch should be removed before the new patch is applied.

Where to apply the patch
Apply the patch to non-irritated and non-irradiated skin on a flat surface of the upper body or upper arms.

Do not apply the patch on:

  • the same place twice in a row
  • areas that you move a lot (joints)
  • skin that is red, burnt or damaged
  • hairy skin

Putting a patch on

Step 1: Preparing the skin

  • Hair at the application site (a hairless area is preferable) should be trimmed with scissors (not shaved) prior to application. The skin should be healthy and undamaged. Do not place the patch onto skin that is red, burnt or damaged.
  • If the site of DUROGESIC application needs to be cleaned before applying the patch, this should be done with clear water. Do not use soaps, oils, or any other cleaners, creams or moisturisers.
  • Make sure your skin is completely dry before the patch is applied. Do not stick a patch on straight after a hot bath or shower. Patches should be inspected prior to use.

Step 2: Open the pouch

  • DUROGESIC patch should be applied immediately upon removal from the sealed package.
  • To remove the patch from the protective pouch, locate the precut notch (indicated by an arrow on the patch label) along the edge of the seal.
  • Fold the pouch at the notch, then carefully tear the pouch material.
  • Inspect the patch for any damage. Patches that are cut, divided, or damaged in any way should not be used.
  • Further open the pouch along both sides, folding the pouch open like a book.

  • The clear plastic protective (release) liner for the patch is slit.
  • Fold the patch in the middle and remove each half of the liner separately.

Step 3: Peel and press

  • Avoid touching the adhesive side of the patch.
  • Apply the patch to the skin by applying light pressure with the palm of the hand for about 30 seconds.
  • Make sure the entire patch is in contact with skin, the corners and the edges of the patch are adhering properly.
  • Then wash hands with clean water.

Step 4: Disposing of the patch

  • As soon as you take a patch off, fold it firmly in half so that the sticky side sticks to itself.
  • Put it back in its original sachet and dispose of the sachet as instructed by your pharmacist.
  • Unused patches should be returned to the pharmacy.
  • 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.

Step 5: Wash

  • Always wash your hands after you have handled the patch using clean water only.

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

Children
DUROGESIC 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.

If you forget to use it

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 receive too much (overdose)

Immediately remove the patch(es) and phone triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then.

Also, phone the Poisons Information Centre for advice, or go to the Emergency Department at your nearest hospital if you think you or anyone else may have used too much DUROGESIC.

Do this even if there are no signs of discomfort or poisoning. The person may need urgent medical attention.

Poisons Information Centre telephone number:

  • Australia: 13 11 26

Keep this telephone number handy.

You should also follow the above steps if someone other than you have accidentally used DUROGESIC that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms:

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

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.

While you are using DUROGESIC

Things you must 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 DUROGESIC. DUROGESIC should not be used during childbirth as the medicine can slow the breathing of the newborn child. Prolonged use of DUROGESIC during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. If you are breast feeding, you should not use DUROGESIC since it may be present in your milk. See your doctor.
  • 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 DUROGESIC patch.
  • Tell your doctor if you develop a fever. At high temperatures, the amount of fentanyl absorbed by the skin increases. Your doctor may need to adjust your DUROGESIC dose
  • If you are about to start taking a new medicine, tell your doctor and pharmacist that you are using DUROGESIC.

Things you must not do

  • 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 DUROGESIC. 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 give the patches to anyone else, even if their symptoms seem similar to yours as they could die from taking it.
  • Do not stop using DUROGESIC unless your doctor advises you to do so. If you have been using DUROGESIC 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 cut, break, chew, crush, dissolve, snort or inject DUROGESIC. This can result in serious side effects and death.

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). Do this even if there are no signs of discomfort or drowsiness.
  • DUROGESIC 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.
  • 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.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects. Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following:

  • nausea, vomiting, constipation, dry mouth, diarrhoea, uncomfortable feeling in stomach or belching after eating, indigestion, blockage in the bowel.
  • low blood pressure, headache, weakness or dizziness, high blood pressure, being less alert or aware, or loss of consciousness.
  • blurred vision
  • 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 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
  • unusual tiredness or weakness, feeling of body temperature change; swelling of the feet, ankles and hands.

Tell your doctor immediately if you notice any of the following as you may need urgent medical care:

  • slow heartbeat.
  • fast heartbeat.

REMOVE the DUROGESIC patch and phone triple zero (000) or go to the Emergency Department at your nearest hospital if the following happens:

  • breathing slows or weakens.
  • temporarily stopped breathing;
  • difficulty in breathing.
  • numbness; seizures or fits.
  • involuntary muscle movements including muscle spasms
  • sweating or trouble urinating
  • sudden life-threatening allergic reaction.
  • sudden signs of allergy such as 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.

Make sure that you are with someone who can keep you awake by talking to you or gently shaking you every now and then. 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 DUROGESIC dose
  • you have not used opioid pain relief before.

Your doctor will carefully select the most appropriate dose for you.

Nausea, vomiting, diarrhoea, anxiety and shivering may occur initially when you are switched from other opioid analgesics to DUROGESIC or if therapy is stopped suddenly. Tell your doctor if you experience any of these effects.

Other side effects not listed above such as sexual dysfunction and withdrawal symptoms may also occur in some people. Tell your doctor if you notice any other effects.

After using DUROGESIC

Storage

Keep DUROGESIC patches in the sealed pouch until it is time to apply them.

Keep the patches in a dry place where temperature stays below 30°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 your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Do not store DUROGESIC patches or any other medicine, in the bathroom or near a sink. Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

The contents of DUROGESIC 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 your doctor tells you to stop using DUROGESIC, or the patches have passed their expiry date, return the patches to your pharmacist.

Product Description

What it looks like

  • DUROGESIC 12 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 12 mcg fentanyl/h" in orange ink.
  • DUROGESIC 25 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 25 mcg fentanyl/h" in red ink.
  • DUROGESIC 50 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 50 mcg fentanyl/h" in green ink.
  • DUROGESIC 75 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 75 mcg fentanyl/h" in blue ink.
  • DUROGESIC 100 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 100 mcg fentanyl/h" in grey ink.

Each pack contains 5 patches.

They are available in five sizes. The number after the name DUROGESIC refers to the amount of fentanyl in micrograms (one thousandth of a milligram) released by the patch per hour.

DUROGESIC 12 micrograms/hour (AUST R 116828)

DUROGESIC 25 micrograms/hour (AUST R 112368)

DUROGESIC 50 micrograms/hour (AUST R 112369)

DUROGESIC 75 micrograms/hour (AUST R 112370)

DUROGESIC 100 micrograms/hour (AUST R 112371)

Ingredients

The patches contain the active ingredient fentanyl.

The patch is made of polyethylene terephalate, ethylene/VA copolymer and polyacrylate adhesive Duro-Tak 87-4287.

Sponsor

Janssen-Cilag Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

This leaflet was prepared in February 2020.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Durogesic

Active ingredient

Fentanyl

Schedule

S8

 

1 Name of Medicine

Fentanyl.

6.7 Physicochemical Properties

Fentanyl is a derivative of 4-anilinopiperidine. It 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 = 3.94. Two polymorphic forms (I and II) have been identified for fentanyl, although polymorphic form II spontaneously converts to polymorphic form I.
N-phenyl- N-[1-(2-phenylethyl)- 4-piperidinyl] propanamide. C22H28N2O. MW: 336.46.

Chemical structure.

Fentanyl has the following structural formula:

CAS number.

437-38-7.

2 Qualitative and Quantitative Composition

The active ingredient in Durogesic is fentanyl.
Durogesic is available in five different strengths. See Table 1.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Durogesic is a fentanyl matrix transdermal system (patch). It is a drug-in-adhesive formulation designed to release fentanyl continuously for 72 hours after application to intact skin. It is available in five different strengths delivering 12, 25, 50, 75 or 100 micrograms/hour fentanyl 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.
Durogesic is a rectangular translucent unit comprising a protective liner and two functional layers. From the outer surface to the surface adhering to skin, these layers include:
a backing of polyethylene terephthalate (PET) film laminated to an ethylene vinyl acetate polymer (EVA);
a drug in adhesive reservoir, which contains 8% by weight fentanyl and 92% by weight acrylate adhesive in the final dried adhesive;
an oversized protective liner of siliconized (PET).
Before use, both parts of the protective liner covering the adhesive layer are removed and discarded. See Figure 1.
Durogesic 12 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 12 mcg fentanyl/h" in orange ink.
Durogesic 25 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 25 mcg fentanyl/h" in red ink.
Durogesic 50 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 50 mcg fentanyl/h" in green ink.
Durogesic 75 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 75 mcg fentanyl/h" in blue ink.
Durogesic 100 micrograms/hour patches are rectangular shape with rounded corners, translucent system with printed border and "Durogesic 100 mcg fentanyl/h" in grey ink.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fentanyl is an opioid analgesic, interacting predominantly with mu-opioid receptors. These mu-binding sites are discreetly distributed in the human brain, spinal cord and other tissues.
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 Durogesic. 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 man indicate that clinically significant histamine release rarely occurs with fentanyl administration. Assays in man show no clinically significant histamine release at doses up to 50 micrograms/kg.

Clinical trials.

Clinical trials were conducted in 542 cancer patients and 847 noncancer patients to evaluate the efficacy of Durogesic 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 noncancer (n = 251) patients, respectively. Durogesic 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 Durogesic over their previous analgesic, such as oral sustained release morphine. The safety of Durogesic has been assessed in 871 cancer patients and 921 noncancer patients. Durogesic 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 Durogesic varied between 25 to 600 micrograms/hour to a maximum continued use of 2 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 Durogesic compared to their previous opioid treatment. One controlled trial involving 88 patients showed no difference in pain control between Durogesic and placebo, however this result may be explained by the short duration of the trial (nine days).
In the chronic noncancer 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 Durogesic 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.

Durogesic provides continuous systemic delivery of fentanyl during the 72 hour application period. Fentanyl is released at a relatively constant rate. The concentration gradient existing between the patch and the lower concentration in the skin drives drug release.
After initial Durogesic application, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours and remaining relatively constant for the remainder of the 72-hour application period.
The serum fentanyl concentrations attained are proportional to the Durogesic patch size. By the end of the second 72-hour application, a steady-state serum concentration is reached and is maintained during subsequent applications of a patch of the same size (see Figure 2). The AUC and Cmax values over a dosing interval at steady state are approximately 40% higher than after a single application.
A pharmacokinetic model has suggested that serum fentanyl concentrations may increase by 14% (range 0-26%) if a new patch is applied after 24 hours rather than the recommended 72-hour application.
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, 50, 75 or 100 micrograms/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. Skin temperature elevation may enhance the absorption of transdermally-applied fentanyl (see Section 4.4 Special Warnings and Precautions for Use). An increase in skin temperature through the application of a heating pad on low setting over the Durogesic system during the first 10 hours of a single application increased the mean fentanyl AUC value by 2.2-fold and the mean concentration at the end of heat application by 61%. Fever may therefore result in a more rapid delivery rate of fentanyl, 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).

Distribution.

Fentanyl is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (3-10 L/kg after intravenous dosing in patients). Fentanyl accumulates in skeletal muscle and fat and is then released slowly into the blood. In a study in cancer patients treated with transdermal fentanyl, plasma protein binding was on average 95% (range 77-100%). Fentanyl crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.

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/h (range 25-75 L/h, n = 8). Individuals vary in their capacity to clear fentanyl. Multiple peaks in serum concentration of fentanyl have been observed during Durogesic administration (see Figure 2).
After Durogesic is 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 IV infusion. Within 72 hours of IV fentanyl administration, approximately 75% of the fentanyl dose 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.

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 Durogesic, 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. Durogesic 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 micrograms/hour application of Durogesic 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.
Based on a population pharmacokinetic model, simulated data in patients with different grades of impaired liver function treated with transdermal fentanyl suggest that the steady-state AUC of patients with Grade B (Child-Pugh Score = 8) and Grade C (Child-Pugh Score = 12.5) liver disease would be approximately 1.36 and 3.72 times larger, respectively, compared with patients with normal liver function (Grade A [Child-Pugh Score 5.5]).
Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of Durogesic 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 Durogesic, 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 Durogesic 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 AUC) were substantially below human therapeutic levels.

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-naïve patients.

4.3 Contraindications

Durogesic is contraindicated in patients with known hypersensitivity to fentanyl or to the adhesives present in the patch.
Durogesic should not be used in the following circumstances because serious or life threatening hypoventilation may occur and can be fatal:
1. in the management of acute or post-operative pain since there is no opportunity for dose titration during short-term use;
2. in the management of mild or intermittent pain that can be managed by nonopioid analgesics or PRN dosing with short acting opioids;
3. at doses exceeding 25 micrograms/hour at the initiation of opioid therapy because of the need to individualise dosing by titrating to the desired analgesic effect.
Durogesic is contraindicated in patients with 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 Durogesic removal or more as clinical symptoms dictate, because serum fentanyl concentrations decline gradually with mean terminal half-life ranging from 20-27 hours.
Durogesic 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 people with substance use disorders. 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, Instructions to the patient; Section 6.6 Special Precautions for Disposal).
The initial Durogesic 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).
Durogesic is not recommended in opioid naïve 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-naïve and not opioid-tolerant states.

Use of Durogesic transdermal system in the opioid naïve patients 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 Durogesic transdermal system is used in initiating therapy in opioid naïve patients, especially in elderly or patients with hepatic or renal impairment. The tendency of tolerance development varies widely among individuals. It is recommended that Durogesic 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-naïve patients.

Hazardous and harmful use.

Durogesic contains the opioid fentanyl and is a potential drug of abuse, misuse and addiction. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Durogesic may result in overdose and/or death. Addiction can occur in patients appropriately prescribed Durogesic at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Durogesic.
All patients receiving opioids should be routinely monitored for signs of 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 Durogesic 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 Durogesic 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 Durogesic 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). 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 naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations (see Section 4.2 Dose and Method of Administration).
Central Nervous System (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.

Durogesic 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.

Durogesic 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. Durogesic 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 Durogesic 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 Durogesic 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 Durogesic patch to direct external heat sources (see Section 4.2 Dose and Method of Administration, Instructions to the patient).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Durogesic, especially by children, can result in a fatal overdose of Durogesic. 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 Durogesic (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 Durogesic 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 Durogesic 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 Durogesic.

Alcohol.

Use of Durogesic in combination with alcoholic beverages and/or other CNS depressants can result in increased risk to the patient. Durogesic 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-naïve 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 receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
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 Durogesic in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, 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.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms, 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 Durogesic should be stopped.

Serotonin syndrome.

Caution is advised when Durogesic 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 reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake 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 Durogesic should be discontinued.

Use in hepatic impairment.

As fentanyl is metabolised to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Durogesic, they should be observed carefully for signs of fentanyl toxicity and the dose of Durogesic 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 Durogesic, 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 clinically 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.
If elderly patients receive Durogesic, they 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 micrograms/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 Durogesic in children has not been established.
Until further experience is gained, Durogesic 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

Based on fentanyl's pharmacodynamic and pharmacokinetic properties, the interactions in Tables 5 and 6 have been identified.

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. Impairment of fertility has been observed in female rats given fentanyl 0.16 mg/kg/day subcutaneously (no effect dose not established) or 0.4 mg/kg/day intravenously (no effect dose 0.1 mg/kg/day, associated with plasma fentanyl concentrations similar to or lower than those expected in humans using 100 micrograms/hour Durogesic 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 Durogesic during pregnancy.
Use of Durogesic during childbirth is not recommended because fentanyl passes through the placenta and may cause respiratory depression in the newborn child, 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 micrograms/hour Durogesic 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, Durogesic is 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 micrograms/hour Durogesic patches. The significance of these findings for potential human risk is unknown.

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 Durogesic 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 a PRN basis (see Section 4.2 Dose and Method of Administration).

Clinical trials data.

The safety of Durogesic was evaluated in 216 subjects who participated in a multicenter, double blind, randomized, placebo controlled clinical trial (FEN-EMA-1) of Durogesic. These subjects took at least one dose of Durogesic and provided safety data. This trial examined patients over 40 years of age with 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 Durogesic by titrating to adequate pain control starting from 25 micrograms/hour to a maximum dose of 100 micrograms/hour in 25 micrograms/hour increments. Adverse drug reactions (ADRs) reported for ≥ 1% of Durogesic treated subjects and with an incidence greater than placebo treated subjects are shown in Table 7.
Adverse drug reactions not reported in Table 7 that were reported by ≥ 1% of Durogesic treated subjects (N = 1854) in 11 clinical trials of Durogesic used for the treatment of chronic malignant or nonmalignant pain (which includes trial FEN-EMA-1) are shown in Table 8. All subjects took at least one dose of Durogesic and provided safety data.
Adverse drug reactions reported by < 1% of Durogesic treated subjects (N = 1854) in the above clinical trial dataset are shown in Table 9.

Postmarketing data.

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience involving all indications with Durogesic are presented below. The adverse drug reactions are ranked by frequency, using the following convention: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100; rare ≥ 1/10,000 to < 1/1000; 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.

Very rare: vision blurred.

Cardiac disorders.

Very rare: tachycardia, bradycardia.

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.

Skin and subcutaneous tissue disorders.

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

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 Durogesic 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 Durogesic (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 Durogesic 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 Durogesic in opioid naïve patients. This information is listed to serve as an alert for the physician.

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.

4.2 Dose and Method of Administration

Dosage (dose and interval).

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).
Durogesic patches should not be cut nor divided. Damaged patches should not be used (see Section 4.4 Special Warnings and Precautions for Use).
Durogesic doses should be individualised based on the status of the patient and should be assessed at regular intervals after application. Body weight, clearance and respiratory function should be considered in selection of initial doses (see Section 4.4 Special Warnings and Precautions for Use). The lowest effective dose should be used.
Durogesic should be applied to nonirritated and nonirradiated skin on a flat surface of the torso or upper arms. Hair at the application site (a nonhairy area is preferable) should be clipped (not shaved) prior to application. If the site of Durogesic 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.
Durogesic 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 Durogesic 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.

Initial dose selection.

The appropriate initiating dose of Durogesic 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. 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 Durogesic, see Equianalgesic potency conversion Table 2. The dosage may subsequently be titrated upwards or downwards, if required, in increments of either 12 or 25 micrograms/hour to achieve the lowest appropriate dose of Durogesic depending on response and supplementary analgesic requirements.

Equianalgesic potency conversion.

To convert from oral or parenteral opioids to Durogesic, 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 2. All intramuscular and oral doses in this chart are considered equivalent to 10 mg of intramuscular morphine in analgesic effect. Table 2 should not be used to convert from Durogesic to other therapies because this conversion to Durogesic is conservative. Use of Table 2 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible.
3. To derive the Durogesic dosage corresponding to the calculated 24 hour, equianalgesic morphine dosage, use the dosage conversion Table 3 or the dosage conversion Table 4 as follows.
4. Table 3 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 4 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 Durogesic 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 Durogesic is attained.

Dose titration and maintenance therapy.

General.

Replace the patch every 72 hours.
If the patch needs to be replaced (e.g. the patch falls off) before 72 hours, apply a patch of the same strength to a different skin site.
This may result in increased serum concentrations of fentanyl (see Section 5.2 Pharmacokinetic Properties) therefore monitor the patient closely.
More than on Durogesic patch may be used for doses greater than 100 micrograms/hour.
At any point during treatment, a patient 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 Durogesic dose exceeds 300 micrograms/hour.

First patch application.

If analgesia is insufficient, during the first application:
replace the Durogesic patch with a patch of the same dose after 48 hours; or
increase the dose when a new patch is applied after 72 hours (see Dose titration below).

Dose titration.

Titrate the dose individually based on the average daily use of supplemental analgesics, until a balance between analgesic efficacy and tolerability is attained.
A 12 microgram/hour strength is available for dose titration. Dosage titration is normally in 12 micrograms/hour or 25 micrograms/hour increments, although the supplementary analgesic requirements (oral morphine 45/90 mg/day is approximately equivalent to Durogesic 12/25 micrograms/hour) and pain status of the patient should be taken into account.
After an increase in dose, it may take up to 6 days for the patient to reach equilibrium on the new dose level. Therefore after a dose increase, patients should wear the higher dose patch through two 72-hour applications before increasing the dose further.

Maintenance therapy.

The principles described under the General subsection above are applicable during maintenance therapy.

Discontinuation of therapy.

If discontinuation of Durogesic is necessary, replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because after system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 20-27 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 3 and Table 4 should not be used to convert from Durogesic 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.

Instructions to the patient.

Durogesic should be kept out of reach of children before, during and after use.
Durogesic 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 Durogesic 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).
Abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Do not share Durogesic with anyone else.

Using and changing the patches.

Make a note of the day, date and time the patch is applied, as a reminder of when it needs to be changed.
There is enough medicine in each patch to last 3 days (72 hours).
Change the patch every third day.
Always remove the old patch before applying the new one.
Always change the patch at the same time of day every 3 days (72 hours).
If more than one patch is used, change all the patches at the same time.

Where to apply the patch.

Durogesic should be applied to nonirritated and nonirradiated skin on a flat surface of the torso or upper arms.
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.

Putting a patch on.

Step 1: Preparing the skin.

Hair at the application site (a nonhairy area is preferable) should be clipped (not shaved) prior to application.
If the site of Durogesic 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.

Step 2: Open the pouch.

Durogesic should be applied immediately upon removal from the sealed package.
To remove the patch from the protective pouch, locate the pre-cut notch (indicated by scissors on the patch label) along the edge of the seal.
Fold the pouch at the notch, and then carefully tear the pouch material.
Inspect the patch for any damage. Patches that are cut, divided, or damaged in any way should not be used.
Further open the pouch along both sides, folding the pouch open like a book.
The protective liner for the patch is slit.
Folding the patch in the middle, and remove each half of the liner separately.

Step 3: Peel and press.

Avoid touching the adhesive side of the patch.
Apply the patch to the skin by applying light pressure with the palm of the hand for about 30 seconds.
Make certain that the edges of the patch are adhering properly.
Then wash hands with clean water.

Step 4: Disposing of the patch.

The 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.
As soon as the patch is taken off, fold it firmly in half so that the sticky side sticks to itself.
Put it back in its original pouch and dispose of the pouch as instructed by the pharmacist.
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.

Step 5: Wash.

Wash hands after handling the patch using clean water only.

External heat sources.

All patients should be advised to avoid exposing the Durogesic 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 dependent 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).

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

Signs and symptoms.

The manifestations of fentanyl overdosage are an extension of its pharmacological actions, the most serious effect being respiratory depression.

Treatment.

For the management of respiratory depression, immediate countermeasures include removing the Durogesic 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 IV 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 Durogesic 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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S8.

6 Pharmaceutical Particulars

6.1 List of Excipients

Duro-Tak 87-4287, ethylene/vinyl acetate copolymer, polyethylene terephthalate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Durogesic patches should be kept out of reach of children. Store in original unopened pouch. Store below 30°C.
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Durogesic securely, in a location not accessible by others.

6.5 Nature and Contents of Container

Durogesic patch is packed in a heat-sealed pouch and is supplied in cartons containing 5 pouches.

6.6 Special Precautions for Disposal

The contents of Durogesic 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. See Section 4.2 Dose and Method of Administration, Instructions to the patient, Disposing of the patch.

Summary Table of Changes