Consumer medicine information

Dutran

Fentanyl

BRAND INFORMATION

Brand name

Dutran

Active ingredient

Fentanyl

Schedule

What is in this leaflet

This leaflet answers some common questions about DUTRAN. 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 DUTRAN against the benefits this medicine is expected to have for you.

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

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

What DUTRAN is used for

DUTRAN is used to relieve chronic or long-lasting pain, which requires strong painkillers.

DUTRAN contains 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 72 hours (3 days). The patch releases a continuous amount of fentanyl that is absorbed through the skin in contact with the patch.

Your doctor may have prescribed DUTRAN for another reason. Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Warning

DUTRAN patches may be retrieved and abused by addicts. 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.

Before you use DUTRAN

When you must not use it

Do not use DUTRAN

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 never had opioid analgesics for pain relief.

Do not use DUTRAN if the packaging is torn or shows signs of tampering. Do not use DUTRAN 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 liver or kidney disease
have or have ever had lung disease
have or have ever had heart disorders
have or have ever had brain lesions or head injuries
have medical conditions which lower your resistance to diseases.

You must tell your doctor if you have not used any opioid analgesics in the past, unless you are being treated for cancer pain. This is because you may be more likely to experience some of the side effects.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using or are given DUTRAN. Tell your doctor if you (or a family member) have ever abused or been dependent on alcohol, prescription medicines, or illegal drugs.

Your doctor will advise you whether or not to use DUTRAN or if you need to adjust the dose or adapt your treatment.

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:

other strong analgesics used to manage pain such as opioids and general anaesthetics.
ritonavir and nelfinavir (used to treat AIDS). Do not take ritonavir or nelfinavir while using DUTRAN, unless you are closely monitored by your doctor.
if taking rifampicin, carbamazepine, phenobarbital, phenytoin, careful monitoring by your doctor and dose adjustment may be required.
antidepressant medicines belonging to the class monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), or serotonin norepinephrine re-uptake inhibitors (SNRIs). DUTRAN should not be used concurrently with these medicines and should be initiated 14 days after cessation of MAOIs. Combination of these medicines with DUTRAN may increase the risk of serotonin syndrome, a potentially life-threatening condition.
certain medicines to treat depression such as nefazodone.
sedating antihistamines.
medicines used as sedatives, hypnotics, sleeping tablets, tranquillisers or muscle relaxants.
Combination of these medicines with DUTRAN may increase the sedative effect of these drugs or slow your ability to react. A change in dose may be required if DUTRAN is used with these medicines.
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 clarithromycin and troleandomycin.
certain medicines to treat fungal infections such as ketoconazole and itraconazole
certain medicines that act on the heart and blood vessels such as calcium-channel blockers like verapamil and dilitiazem.
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 on driving and operating machinery
DUTRAN can affect your alertness and ability to drive and operate machinery. Do not drive or operate machinery until your doctor says it is safe.

Effect of alcohol
Avoid alcohol when using DUTRAN since their combined effect may cause drowsiness.

Tolerance

As with all opioid analgesics, DUTRAN may lead to tolerance with continued use. Your doctor may, therefore, prescribe a higher dose of DUTRAN after some time to continue to give you pain relief.

Using DUTRAN

How to use the patch

Adults
DUTRAN is available in five different sizes. Your doctor will decide which patch, or combination of patches, is suitable to control your pain.

Each patch is applied onto the skin and lasts for three days (72 hours).
After three days, remove the patch and apply a new patch to the skin at a different place.

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

Children
DUTRAN 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.

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

Find an intact and hairless spot of skin on the upper part of your body or on your upper arm. The skin should be healthy and undamaged. Do not place the patch onto skin that is red, burnt or damaged.
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.
DUTRAN should be applied immediately upon removal from the protective pouch. After locating the tear mark at the edge of the pouch, it should be carefully torn open and the patch removed.
Each DUTRAN has a clear plastic protective liner that can be peeled off in two pieces. After folding the patch in the middle, peel off each part of the protective liner separately. 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.

Never cut or divide the patch. Do not use a patch that has been divided, cut or damaged in any way.

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 DUTRAN correctly and remember when the next patch is due.

Your doctor may prescribe additional pain relievers to control occasional outbreaks of pain.

Changing the patch

After three days (72 hours), remove the patch.
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.
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 DUTRAN.

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)

The most important sign of overdose is difficulty in breathing.

If a person using DUTRAN has abnormally slow or weak breathing, remove the patch. Keep the person awake by talking to them or gently shaking them every now and then.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to the Emergency Department at your nearest hospital.

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

Information for the doctor in case of overdose: inject with naloxone and transfer patient to hospital.

Please refer to full Product Information for details on appropriate management of overdose.

While you are using DUTRAN

Things you must do

Always follow your doctor's instructions carefully.
Tell your doctor if you become pregnant while using DUTRAN.
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 DUTRAN.
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 DUTRAN dose.
If you are about to start taking a new medicine, tell your doctor and pharmacist that you are using DUTRAN.

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 DUTRAN. 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 use DUTRAN to treat any other complaint unless your doctor says so.
Do not give the patches to anyone else, even if their symptoms seem similar to yours.
Do not stop using DUTRAN unless your doctor advises you to do so. If you have been using DUTRAN for a long period of time but stop using it suddenly without your doctor's advice, you may experience withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety and shivering). Seek your doctor's advice if you experience these symptoms.

Things to be careful of

If the patch accidentally adheres to another person (for example a family member sharing the same bed), remove the patch and contact your doctor. 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.

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 of 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.
sweating or trouble in 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.
skin rash (local redness and itch at the site of the patch is usually mild and resolves when the patch is removed).
unusual tiredness or weakness, feeling of body temperature change.

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

slow heart beat.
fast heart beat.

REMOVE the DUTRAN patch and tell your doctor immediately or go to the Emergency Department at your nearest hospital if the following happens:

breathing slows or weakens.
temporarily stopped breathing;
difficulty in 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. Nausea, vomiting, diarrhoea, anxiety and shivering may occur initially when you are switched from other opioid analgesics to DUTRAN or if therapy is stopped suddenly. Tell your doctor if you experience any of these effects. Medicines like DUTRAN can lead to addiction. This is unlikely when DUTRAN is used correctly. Other side effects not listed above, sexual dysfunction and withdrawal symptoms, may also occur in some people. Tell your doctor if you notice any other effects.

After using DUTRAN

Storage

Keep the 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.

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 DUTRAN 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 the patches may be retrieved and abused by addicts.

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

If your doctor tells you to stop using DUTRAN, or the patches have passed their expiry date, return the patches to your pharmacist.

Product description

What it looks like

DUTRAN patches are rectangular, round-cornered, transparent patches imprinted with:

'fentanyl 12µg/h' for the 12 micrograms/hour strength
'fentanyl 25µg/h' for the 25 microgram/hour strength
'fentanyl 50µg/h' for the 50 microgram/hour strength
'fentanyl 75µg/h' for the 75 microgram/hour strength
'fentanyl 100µg/h' for the 100 microgram/hour strength

Each pack contains 5 patches. Each patch is in a sealed pouch.

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

Ingredients

The patches contain the active ingredient fentanyl.

The patch is composed of polyacrylate adhesive.

Australian Registration numbers

DUTRAN 12 (AUST R 192231)

DUTRAN 25 (AUST R 190790)

DUTRAN 50 (AUST R 190791)

DUTRAN 75 (AUST R 190792)

DUTRAN 100 (AUST R 190793)

Supplier

Amneal Pharma Australia Pty Ltd
12 River St
South Yarra VIC 3141

This leaflet was prepared in October 2017

Published by MIMS December 2017

BRAND INFORMATION

Brand name

Dutran

Active ingredient

Fentanyl

Schedule

1 Name of Medicine

Fentanyl.

6.7 Physicochemical Properties

Chemical name: N-phenyl- N-[1-(2-phenylethyl)- 4-piperidinyl] propanamide.

Molecular formula and molecular weight.

Molecular formula: C₂₂H₂₈N₂O. MW: 336.46.

Chemical structure.

CAS number.

437-38-7.
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 = 3.94. Two polymorphic forms (I and II) have been identified for fentanyl, although polymorphic form II spontaneously converts to polymorphic form I.

2 Qualitative and Quantitative Composition

Dutran is available in five different strengths delivering fentanyl 12, 25, 50, 75 or 100 microgram/hour to the systemic circulation.

Dutran 12.

Each transdermal patch with 3.75 cm² active surface area contains 2.063 mg fentanyl with a release rate of 12 microgram fentanyl per hour (over a period of 3 days) and is supplied in a sealed pouch; 5's.

Dutran 25.

Each transdermal patch with 7.5 cm² active surface area contains 4.125 mg fentanyl with a release rate of 25 microgram fentanyl per hour (over a period of 3 days) and is supplied in a sealed pouch; 5's.

Dutran 50.

Each transdermal patch with 15 cm² active surface area contains 8.25 mg fentanyl with a release rate of 50 microgram fentanyl per hour (over a period of 3 days) and is supplied in a sealed pouch; 5's.

Dutran 75.

Each transdermal patch with 22.5 cm² active surface area contains 12.375 mg fentanyl with a release rate of 75 microgram fentanyl per hour (over a period of 3 days) and is supplied in a sealed pouch; 5's.

Dutran 100.

Each transdermal patch with 30 cm² active surface area contains 16.5 mg fentanyl with a release rate of 100 microgram fentanyl per hour (over a period of 3 days) and is supplied in a sealed pouch; 5's.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dutran 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. The matrix from which fentanyl is released consists of polyacrylate cross-linked with titanium (Durotak 387-2510, Proprietary Ingredient ARTG Number 106231). The patches also incorporate a backing liner (polypropylene) and a release liner (polyethylene terephthalate). 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.
Dutran is a rectangular, round cornered, transparent and colourless patch contained in a protective pouch made from composite foil. The pouch is made by sealing two parts of the composite foil together.
Before use, the patch is removed from the protective pouch.

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 discretely 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 naïve patients with acute pain. Minimum effective analgesic serum concentrations of fentanyl in opioid naïve patients range from 0.3 to 1.5 nanogram/mL and are reached approximately six hours after application of the patch. Adverse reactions increase in frequency at serum concentrations above 2.0 nanogram/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 nanogram/mL in opioid naïve 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 weal 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 patches 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. 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 patches were 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 patches 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 patches compared to their previous opioid treatment. One controlled trial involving 88 patients showed no difference in pain control between fentanyl patches 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 fentanyl patches provide 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. 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. 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 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 fentanyl patch application, 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 concentrations 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 (CYP3A4) 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 hepatic 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 patch 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 the fentanyl patch 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 intravenous infusion.

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 patches, 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 the elderly, cachectic or debilitated patients as they may have altered pharmacokinetics due to fat storage, muscle wasting, or altered clearance.
If fentanyl is used in the 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 fentanyl patch were assessed. Although t_max and t_1/2 were not altered, the mean plasma C_max 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 fentanyl is used in patients with renal impairment, the patients 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 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.

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

Known hypersensitivity to fentanyl or to the adhesives present in the patch.
Dutran 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;
in the management of mild or intermittent pain that can be managed by nonopioid analgesics or 'as required' dosing with short acting opioids;
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.
Dutran is contraindicated for use 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 up to 24 hours after patch removal since serum fentanyl concentrations decline gradually with mean terminal half-life ranging from 22 to 25 hours.
Dutran 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 4.4 Special Warnings and Precautions for Use, Instructions to patients).
The initial Dutran 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). Dutran 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.

Hazardous and harmful use.

Dutran 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 Dutran may result in overdose and/or death. Addiction can occur in patients appropriately prescribed Dutran 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 Dutran.
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 Dutran with anyone else.

Opioid naïve and not opioid tolerant states.

Use of a fentanyl transdermal system in the opioid naïve 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 the fentanyl 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 Dutran 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.

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 Dutran 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, in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma) and in patients with decreased clearance of fentanyl due to hepatic or renal impairment. 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), 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).

Chronic pulmonary disease.

Dutran 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.

Head injuries and increased intracranial pressure.

Dutran 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. Dutran 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 Dutran 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 Dutran 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 Dutran patches to direct external heat sources (see Section 4.4 Special Warnings and Precautions for Use, Instructions to patients).

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 Dutran 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 Dutran 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 Dutran.

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.
Dutran 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. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Dutran may result in overdose and/or death. Patients at increased risk of opioid abuse may still be appropriately treated with modified release opioid formulations; however, these patients will require monitoring for signs of misuse, abuse or addiction.
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 Dutran 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; Section 4.2 Dose and Method of Administration).

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.

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).

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.

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 patches should be stopped.

Serotonin syndrome.

Caution is advised when Dutran 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]). 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 patches should be discontinued.

Instructions to patients.

Dutran should be kept out of reach of children before, during and after use.
Only one patch of Dutran should be worn at a time unless there is a specific need otherwise (e.g. 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. 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).
Abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Do not share Dutran with anyone else.

Application site.

Fentanyl patch 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 Dutran 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 (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 sunbaking altogether.

Instructions for use / handling.

Dutran should be applied immediately upon removal from the protective pouch. The patch should be first removed from the protective liner. After locating the tear mark at the edge of the pouch, it should be carefully torn open and the patch 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 10 to 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 Dutran 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 while 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 ingestion/ exposure.

The patch must only be used by the person for whom it was prescribed. Accidental ingestion or exposure to Dutran, 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 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). Patients and their caregivers should be given information on safe storage and disposal of unused Dutran (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

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.

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 Dutran, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Use in hepatic impairment.

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

Use in the elderly, cachectic or debilitated patients.

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 fentanyl patches, 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 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 Dutran in children have not been established. Until further experience is gained, Dutran 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.

Not 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 other central nervous system depressants, including opioids, benzodiazepines, gabapentinoids, cannabis, tricyclic antidepressants, antipsychotics, centrally-active anti-emetics, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquillizers, skeletal muscle relaxants, monoamine oxidase inhibitors, antihistamines and alcoholic beverages, may produce additive depressant effects. Hypoventilation, hypotension and profound sedation or coma may occur. Therefore, the use of any of these drugs concomitantly with Dutran requires special care. 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).

Dutran is not recommended for use in patients who require the concomitant administration of an MAOI. Severe and unpredictable interactions with MAOIs, involving the potentiation of opiate effects or the potentiation of serotonergic effects, have been reported. Therefore, fentanyl patches should not be used within 14 days after discontinuation of treatment with MAOIs.

Serotonergic drugs.

Coadministration of fentanyl with a serotonergic agent, such as a Selective Serotonin Reuptake Inhibitor (SSRI) or a Serotonin Norepinephrine Reuptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition.

Interactions with CYP3A4 inhibitors.

Fentanyl is metabolised mainly via the human CYP3A4 enzyme. The concomitant use of Dutran with CYP3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, 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. 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 patients are closely monitored, particularly for signs of respiratory depression, and reduction of the dose of Dutran may be required.

Interactions with CYP3A4 inducers.

The concomitant use 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.

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 Dutran 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 post-natal 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 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 the newborn / infant. Therefore, Dutran 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 fentanyl 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 Dutran 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 multicenter, double-blind, randomized, placebo-controlled clinical trial (FEN-EMA-1) of fentanyl patches. These subjects took at least one dose of fentanyl patch 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 fentanyl patches 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 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 worldwide postmarketing experience involving all indications with fentanyl patches 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.

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.

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.

General disorders and administration site conditions.

Very rare: drug withdrawal syndrome, asthenia, application site reaction, feeling of body temperature change, pyrexia.
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 or if therapy is stopped suddenly (see Section 4.2 Dose and Method of Administration).
As with other opioid analgesics, tolerance, physical dependence and psychological dependence can develop on repeated use of fentanyl patches (see Section 4.4 Special Warnings and Precautions for Use). There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used fentanyl 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 patches in opioid naïve 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.

4.2 Dose and Method of Administration

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).
Dutran patches should not be cut nor divided. Damaged patches should not be used (see Section 4.4 Special Warnings and Precautions for Use).
Dutran 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).
Dutran 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 Dutran 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. Dutran 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 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 Dutran 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 Dutran 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 Dutran, refer to Equianalgesic potency conversion (Table 1). 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 Dutran depending on response and supplementary analgesic requirements.

Equianalgesic potency conversion.

To convert from oral or parenteral opioids to Dutran, the following procedures should be applied:
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 Dutran to other therapies because this conversion to Dutran 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. To derive the Dutran dosage corresponding to the calculated 24-hour, equianalgesic morphine dosage, use the dosage-conversion Table 2 or the dosage-conversion Table 3 as follows:
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).
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 Dutran 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 Dutran is attained.

Dose titration and maintenance therapy.

Each patch should be replaced every 72 hours. The dose should be titrated individually until a balance between 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 Dutran 12/25 microgram/hour) and pain status of the patient should be taken into account. More than one 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 Dutran dose exceeds 300 microgram/hour.

Discontinuation of therapy.

As fentanyl levels decrease gradually after the 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 of dose adjustment (see Section 4.8 Adverse Effects (Undesirable Effects)). Tables 2 and 3 should not be used to convert from Dutran to other therapies to avoid overestimating the new analgesic dose and potentially causing overdose.

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

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 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 re-narcotisation 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 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.
Contact the Poison Information Centre on 13 11 26 (Australia) for advice on the management of overdosage.

7 Medicine Schedule (Poisons Standard)

S8.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients: DURO-TAK 387-2510 (PI 106231), polypropylene, polyethylene terephthalate and titanium dioxide.

6.2 Incompatibilities

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 Australia Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.