1. NAME OF THE MEDICINAL PRODUCTS

Tilofyl 25 microgram/hour transdermal patches

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Tilofyl 25 microgram/hour transdermal patches

Each transdermal patch (active surface area 10 cm²) contains 2.5 mg fentanyl (corresponding to 25 microgram/hour fentanyl release rate).

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM Transdermal patch

Transparent and oblong transdermal patch which consists of a protective layer (to be removed prior to application of the patch) and four functional layers: an occlusive backing, a drug reservoir, a release membrane and an adhesive surface.

Surface area of the transdermal patch:

Tilofyl 25 microgram/hour transdermal patches: 10 cm2

4.1 Therapeutic indications

Adults:

Chronic severe pain requiring treatment with opioid analgesics, e.g. cancer pain.

Children:

Long term management of severe chronic pain in children receiving opioid therapy from 2 years of age.

4.2. Posology and method of administration

Tilofyl transdermal patches release fentanyl over 72 hours. The fentanyl release rate is 25 microgram/hour and the corresponding active surface area is 10 cm².

The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.

Posology

Adults:

Initial dose selection:

The appropriate initiating dose of Tilofyl should be based on the patient's current opioid use. 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.

Patients receiving opioid treatment for the first time

In opioid-naive patients, who have not previously been treated with opioids, the initial dosage should not exceed 25 microgram/hour.

Clinical experience with fentanyl transdermal patches is limited in opioid-naive patients. In the circumstances in which therapy with Tilofyl is considered appropriate in opioid-naive patients, it is recommended that these patients be titrated with low doses of immediate release opioids (e.g., morphine) to attain equianalgesic dosage relative to Tilofyl with a release rate of 25 micrograms/hour. Patients can then be converted to Tilofyl 25 microgram/hour. The dose may subsequently be titrated upwards, if required, to achieve the lowest appropriate dose of Tilofyl depending on the response and supplementary analgesic requirements.

In opioid-naive older or weak patients, it is not recommended to initiate an opioid treatment with fentanyl transdermal patches, due to their known susceptibility to opioid treatments. In these cases, it would be preferable to initiate a treatment with low doses of immediate release morphine and to prescribe Tilofyl after determination of the optimal dosage.

Changing from other opioid treatment

When changing over from oral or parenteral opioids to fentanyl treatment, the initial dosage should be calculated as follows:

1.    The quantity of analgesics required over the last 24 hours should be determined.

2.    The obtained sum should be converted to the corresponding oral morphine dosage using Table 1

3.    The corresponding fentanyl dosage should be determined as follows:

a)    using Table 2 for patients who have a need for opioid rotation (conversion ratio of oral morphine to transdermal fentanyl equal to 150:1)

b)    using Table 3 for patients on stable and well tolerated opioid therapy (conversion ratio of oral morphine to transdermal fentanyl equal to 100:1).

Table 1: Equianalgesic potency conversion

All i.m. and oral dosages given in the table are equivalent in analgesic effect to 10 mg morphine administered intramuscularly.

Active substance	Equianalgesic doses (mg)
	i.m.1	Oral
Morphine	10	30-40 (assuming repeated dosing)
Hydromorphone	1.5	7.5
Methadone	10	20
Oxycodone	15	30
Levorphanol	2	4
Oxymorphone	1	10 (rectal)
Diamorphine	5	60
Pethidine	75	-
Codeine	130	200
Buprenorphine	0.4	0.8 (sublingual)
Ketobemidone	10	20-30

Table 2: Recommended initial dosage of Tilofyl transdermal patch based upon the oral daily morphine dosage (for patients who have a need for opioid rotation)

Oral	Dosage of
morphine	Tilofyl transdermal patch
(mg/24 h)	(microgram/hour)
90-134	25
135-224	50
225-314	75
315-404	100
405-494	125
495-584	150
585-674	175
675-764	200
765-854	225
855-944	250
945-1034	275
1035-1124	300
Table 3: Recommended initial dosage of Tilofyl transdermal patch based upon the oral
daily morphine dosage (for patients on	stable and well tolerated opioid therapy)
Oral	Dosage of
morphine	Tilofyl transdermal patch
(mg/24 h)	(microgram/hour)
60-89	25
90-149	50
150-209	75
210-269	100
270-329	125
330-389	150
390-449	175
450-509	200
510-569	225
570-629	250
630-689	275
690-749	300
The oral morphine dosages in Table 2 and 3 were used as a basis in clinical trials when changing medication to fentanyl transdermal patches. Other conversion schemes which have proved their usefulness in clinical practice exist and may be applied.
Previous analgesic therapy should be phased out gradually from the time of the first patch application until analgesic efficacy with Tilofyl is attained. For both strong opioid-naive and opioid tolerant patients, the initial evaluation of the analgesic effect of Tilofyl should not be made until the patch has been worn for 24 hours due to the gradual increase in serum fentanyl
concentrations up to this time.

Dose titration and maintenance therapy

The Tilofyl transdermal patch should be replaced every 72 hours. The dose should be titrated individually until the analgesic efficacy is attained. In patients who experience a marked decrease in analgesia in the period of 48-72 hours after application, replacement of the Tilofyl transdermal patch after 48 hours may be necessary. If analgesia is insufficient at the end of the initial application period, the dose may be increased at intervals of 3 days, until the desired effect is obtained for each patient. The dosage is normally raised in increments of 25 microgram/hour (oral morphine 90 mg/day ~ Tilofyl 25 micrograms/h), but the need for additional medication and the pain experienced by the patient should be taken into account. When the required dosage exceeds 100 microgram/hour, more than one Tilofyl transdermal patch may be used to achieve the desired dose. Patients may require periodic supplemental doses of a short-acting analgesic for "breakthrough" pain. Additional or alternative methods of analgesia should be considered when the transdermal fentanyl dose exceeds 300 microgram/hour.

Conversion or discontinuation of treatment

If discontinuation of Tilofyl is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl serum concentrations fall gradually after Tilofyl is removed, it takes 17 hours or more for the fentanyl serum concentrations to decrease 50% (see section 5.2). As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms.

Opioid withdrawal symptoms (see section 4.8) are possible in some patients after conversion or dose adjustment.

Tables 2 and 3 should not be used to convert from Tilofyl to other therapies to avoid overestimating the new analgesic dose and potentially causing overdose.

Use in older patients

Older patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see sections 4.4 and 5.2).

Paediatric population

Children aged 16 years and above: follow adult dosage.

Children aged 2 to 16 years old:

Tilofyl should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 45 mg oral morphine equivalents per day. A lower starting dose and the titration schedule in children may require a fentanyl release rate of less than 25 microgram/hour. In the case of Tilofyl, due to the dose strengths of this product starting at 25 microgram/hour, use in children is not recommended and use of other fentanyl transdermal patches should be considered.

To convert paediatric patients from oral opioids to Tilofyl refer to Table 4.

Table 4: Recommended fentanyl transdermal patch dose based upon daily oral

morphine dose¹_

Oral 24-hour morphine    Fentanyl transdermal patch

(mg/day)_(microgram/hour)_

For paediatric patients²_

30 - 44    12.5

45 - 134    25

¹    In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal patches

²    Conversion to Tilofyl doses greater than 25 micrograms/h is the same for adult and paediatric patients

For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 44 mg oral morphine per day or its equivalent opioid dose was replaced by one fentanyl transdermal patch 12.5 microgram/hour. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to Tilofyl. The conversion schedule should not be used to convert from Tilofyl into other opioids, as overdosing could then occur.

The analgesic effect of the first dose of Tilofyl will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Tilofyl, the patient should be given the previous regular dose of analgesics. In the next 12 hours, these analgesics should be provided based on clinical need.

Since peak fentanyl levels occur after 12 to 24 hours of treatment, monitoring of the paediatric patient for adverse events, which may include hypoventilation, is recommended for at least 48 hours after initiation of Tilofyl therapy or up-titration of the dose (see also section 4.4).

Dose titration and maintenance

If the analgesic effect of Tilofyl is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to increase the dose of transdermal fentanyl. Dose adjustments should be done in 12.5 microgram/hour steps. Due to the dosage strengths of this product, starting at 25 microgram/hour, other fentanyl transdermal patches with lower dosages should be used.

Use in patients with hepatic or renal impairment

Patients with impaired hepatic or renal function should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.4).

Use in febrile patients

Dose adjustment may be necessary in patients during episodes of fever (see section 4.4).

Method of administration For transdermal use.

Tilofyl transdermal patch should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arm. In young children, the upper back is the preferred location to apply the patch, to minimise the potential of the child removing the patch. A non-hairy area should be selected. If this is not possible, hair at the application site should be clipped (not shaved) prior to system application. If the site of application requires to be cleansed prior to application of the patch, this should be done with water. Soaps, oils, lotions, alcohol or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before application of the patch.

Since the transdermal patch is protected outwardly by a waterproof covering foil, it may also be worn when taking a shower.

Tilofyl transdermal patch is to be attached as soon as the pack has been opened. Following removal of the protective layer, the transdermal 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. An additional fixing of the transdermal patch may be necessary.

Duration of administration

The patch should be changed after 72 hours. If an earlier change becomes necessary in individual cases, no change should be made before 48 hours have elapsed, otherwise a rise in mean fentanyl concentrations may occur. A new skin area must be selected for each application. A period of 7 days should be allowed to elapse before applying a new patch to the same area of skin. The analgesic effect may persist for some time after removal of the transdermal patch.

If traces of the transdermal patch remain on the skin after removal of the patch, these can be cleaned off using copious amounts of soap and water. No alcohol or other solvents must be used for cleaning as these may penetrate the skin due to the effect of the patch.

4.3.    Contraindications

-    Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

-    Acute or postoperative pain, since dosage titration is not possible during short-term use and because serious and life-threatening hypoventilation could result

-    Severly impaired central nervous system function

-    Severe 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 TILOFYL REMOVAL OR MORE AS CLINICAL SYMPTOMS DICTATE BECAUSE SERUM FENTANYL CONCENTRATIONS DECLINE GRADUALLY AND ARE REDUCED BY ABOUT 50% 17 (RANGE 13-22) HOURS LATER.

Fentanyl transdermal patches should be kept out of reach of children at all times before and after use.

Tilofyl should not be divided, cut or damaged in any other way, since this would result in the uncontrolled release of fentanyl. A patch that has been divided, cut or damaged in any way should not be used.

It is not possible to ensure the interchangeability of different makes of fentanyl transdermal patches in individual patients. Therefore, it should be emphasised that patients should not be changed from one make of fentanyl transdermal patches to another without specific counselling on the change from their healthcare professionals.

Breakthrough pain

Studies have shown that almost all patients, despite treatment with a fentanyl transdermal patch, require supplemental treatment with potent rapid-release medicinal products to arrest breakthrough-pain.

Respiratory depression

As with all potent opioids, some patients may experience significant respiratory depression with fentanyl transdermal patches; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the transdermal patch. The incidence of respiratory depression increases as the fentanyl dose is increased (see also section 4.9). CNS active substancess may increase the respiratory depression (see section 4.5).

Opioid-naive and not opioid-tolerant states

Use of fentanyl transdermal patch in opioid-naive 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 fentanyl transdermal system is used in initiating therapy in opioid-naive patients. It is recommended that

fentanyl transdermal patch be used in patients who have demonstrated opioid tolerance (see section 4.2).

Chronic pulmonary disease

Fentanyl 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.

Drug dependence and potential for abuse

Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is rare. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of fentanyl transdermal patch may result in overdose and/or death.

Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. 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.

Increased intracranial pressure

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

Cardiac diseases

Fentanyl may cause bradycardia and should therefore be administered with caution to patients with bradyarrhythmias.

Opioids may cause hypotension, especially in patients with acute hypovolaemia. Underlying, symptomatic hypotension and/or hypovolaemia should be corrected before treatment with fentanyl transdermal patches is initiated.

Hepatic impairment

Because fentanyl is metabolised to pharmacologically inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Tilofyl, they should be observed carefully for signs of fentanyl toxicity and the dose of Tilofyl reduced if necessary (see section 5.2).

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 kidneys. If patients with renal impairment receive Tilofyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).

Fever/external heat application

A pharmacokinetic model suggests that serum fentanyl concentrations may increase by about one-third if the skin temperature increases to 40 °C. Therefore, patients with fever should be monitored for opioid side effects and the fentanyl transdermal patch dose should be adjusted if necessary. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. A clinical pharmacology trial conducted in healthy adult subjects has shown that the application of heat over the fentanyl transdermal patch system increased mean fentanyl AUC values by 120% and mean C_max values by 61%.

All patients should be advised to avoid exposing the fentanyl transdermal patch application site to direct external 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

whirlpool spa baths.

Serotonin syndrome

Caution is advised when fentanyl transdermal patches are coadministered with medicinal products that affect the serotonergic neurotransmitter systems. The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic active substances such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with active substances which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyper-reflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g, nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, rapid discontinuation of Tilofyl should be considered. Interactions with CYP3A4 inhibitors

The concomitant use of transdermal fentanyl with cytochrome P450 (CYP)3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole, fluconazole, voriconazole, troleandomycin, clarithromycin, erythromycin, 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. 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 patient is closely monitored. Patients, especially those who are receiving fentanyl transdermal patches and CYP3A4 inhibitors, should be monitored for signs of respiratory depression and dosage adjustments should be made if warranted.

Accidental exposure by patch transfer

Accidental transfer of a fentanyl transdermal patch to the skin of a 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 nonpatch wearer (see section 4.9).

Use in older patients

Data from intravenous studies with fentanyl suggest that older patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the active substance than younger patients. If older patients receive Tilofyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).

Paediatric population

Fentanyl transdermal patch should not be administered to opioid naive paediatric patients

(see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of transdermal fentanyl administered.

Transdermal fentanyl has not been studied in children under 2 years of age. Tilofyl should be administered only to opioid-tolerant children aged 2 years or older (see section 4.2). Tilofyl should not be used in children under 2 years of age.

To guard against accidental ingestion by children, use caution when choosing the application site for Tilofyl (see sections 4.2 and 6.6) and monitor adhesion of the patch closely.

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 Tilofyl should be stopped.

Patients with myasthenia gravis

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

For disposal instructions see section 6.6.

4.5. Interaction with other medicinal products and other forms of interaction

Other central nervous system depressants

Fentanyl may produce additive depressant effects with other central nervous system depressants, including:

•    opioids

•    sedatives

•    hypnotics

•    general anaesthetics

•    phenothiazines

•    anxiolytics and tranquillizer

•    antipsychotics

•    skeletal muscle relaxants

•    sedating antihistamines

•    alcoholic beverages

Concomitant use may result in hypoventilation, hypotension, profound sedation, coma or death. Therefore, the use of any of the above mentioned concomitant medicinal products requires special patient care and observation. Dose reduction of one or both medicinal products should be taken into consideration.

CYP3A4 inhibitors

Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.

The concomitant use of transdermal fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir, ketoconazole, itraconazole, fluconazole, voriconazole, troleandomycin, clarithromycin, erythromycin, 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. In this situation, special patient care and observation are appropriate. The concomitant use of CYP3A4 inhibitors and transdermal fentanyl is not recommended, unless the patient is closely monitored (see section 4.4).

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.

Monoamine Oxidase Inhibitors (MAOI)

Fentanyl transdermal patch 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 serotoninergic effects, have been reported. Therefore, Tilofyl should not be used within 14 days after discontinuation of treatment with MAOIs.

Serotonergic medicinal products

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

Concomitant use of mixed agonists/antagonists

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

4.6. Pregnancy and lactation

Pregnancy

There are no adequate data from the use of fentanyl transdermal patch in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Fentanyl crosses the placenta. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl transdermal patch during pregnancy. Tilofyl should not be used during pregnancy unless clearly necessary.

Use of fentanyl transdermal patch during childbirth is not recommended because it should not be used in the management of acute or postoperative pain (see section 4.3). Moreover, because fentanyl passes through the placenta, the use of Tilofyl during childbirth might result in respiratory depression in the newborn infant.

Breast-feeding

Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breastfed infant. Breast-feeding should therefore be discontinued during treatment with Tilofyl and for at least 72 hours after removal of the patch.

4.7. Effects on ability to drive and use machines

Tilofyl may impair the mental and/or physical ability required to perform potentially hazardous tasks such as driving a car or operating machinery. Patients stabilized on a specific dosage -without further interference from other medicinal products - will not necessarily be restricted. Caution is required especially at the beginning of treatment, at dosage increases as well as in connection with other medicinal products since the ability to drive and use machines may be impaired.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if: o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

4.8. Undesirable effects

The safety of fentanyl transdermal patches was evaluated in 1854 adult and paediatric subjects who participated in 11 clinical trials (double-blind fentanyl patch [placebo or active control] and/or open label fentanyl patch [no control or active control]) used for the management of chronic malignant or non-malignant pain. These subjects took at least 1 dose of fentanyl transdermal patch and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported adverse drug reactions (ADRs) were (with % incidence): nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).

The most serious undesirable effect of fentanyl is respiratory depression.

The ADRs reported with the use of fentanyl transdermal patches from these clinical trials, including the above-mentioned ADRs, and from post-marketing experiences are listed below.

The displayed frequency categories use the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data).

System organ class	Adverse drug reactions
	F requency category
	Very Common	Common	Uncommon	Rare	Not known
Immune system disorders		Hypersensitivit y			Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction
Metabolism and nutrition disorders		Anorexia
Psychiatric disorders		Insomnia, Depression, Anxiety, Confusional state, Hallucination	Agitation, Disorientation, Euphoric mood

System organ class	Adverse drug reactions
	F requency category
	Very Common	Common	Uncommon	Rare	Not known
Nervous system disorders	Somnolence, Dizziness, Headache1	Tremor, Paraesthesia	Hypoaesthesia, Convulsion (including clonic convulsions and grand mal convulsion), Amnesia, Depressed level of consciousness, Loss of consciousness
Eye disorders			Blurred vision	Miosis
Ear and labyrinth disorders		Vertigo
Cardiac disorders		Palpitations, Tachycardia	Bradycardia, Cyanosis	Arrythmia
Vascular disorders		Hypertension	Hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnoea	Respiratory depression, Respiratory distress	Apnoea, Hypoventil ation	Bradypnoea
Gastrointestinal disorders	Nausea1, Vomiting1, Constipation1	Diarrhoea1, Dry mouth, Abdominal pain, Upper abdominal pain, Dyspepsia	Ileus	Subileus
Skin and subcutaneous tissue disorders		Hyperhidrosis, Pruritus1, Rash, Erythema	Eczema, Allergic dermatitis, Skin disorder, Dermatitis, Contact dermatitis
Musculoskeleta l and connective tissue disorders		Muscle spasms	Muscle twitching
Renal and urinary disorders		Urinary retention

System organ class	Adverse drug reactions
	F requency category
	Very Common	Common	Uncommon	Rare	Not known
Reproductive system and breast disorders			Erectile dysfunction, Sexual dysfunction
General disorders and administration site conditions		Fatigue, Peripheral oedema Asthenia, Malaise, Feeling cold	Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivity Drug withdrawal syndrome2, Pyrexia	Application site dermatitis, Application site eczema

¹    see “paediatric subjects” below

²    see “description of selected adverse reactions” below

Description of selected adverse reactions

As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can develop on repeated use of fentanyl transdermal patches (see section 4.4).

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 transdermal patch or if therapy is stopped suddenly (see section 4.2).

There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used fentanyl transdermal patches during pregnancy (see section 4.6).

Paediatric population

The adverse event profile in children and adolescents treated with fentanyl transdermal patch was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with fentanyl transdermal patch use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, headache, vomiting, nausea, constipation, diarrhoea and pruritus.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at http://www.yellowcard.mhra.gov.uk.

4.9. Overdose

Symptoms

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

Treatment

For management of respiratory depression, immediate countermeasures include removing the Tilofyl transdermal 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 the opioid antagonist. The interval between IV 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.

If the clinical situation warrants, a patent airway should be established and maintained, possibly with an oropharyngeal airway or endotracheal tube, and 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.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: analgesics, opioids, phenylpiperidine derivatives ATC code: N02AB03

Fentanyl is an opioid analgesic which interacts predominantly with the p-opioid receptor. Its principal therapeutic effects are analgesia and sedation. The serum concentrations of fentanyl that cause a minimal analgesic effect in opioid-naive patients fluctuate between 0.3-1.5 ng/ml. The incidence of adverse effects increases when serum concentrations exceed 2 ng/ml. The concentration causing adverse reactions increases with the duration of exposure. The tendency to develop tolerance shows considerable inter-individual variety.

Paediatric population

The safety of transdermal fentanyl was evaluated in three open-label trials in 293 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged to 2 to 6 years. In these studies, 30 mg to 44 mg oral morphine per day was replaced by one fentanyl 12.5 microgram/hour transdermal patch. Starting dose of 25 microgram/hour and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg of oral morphine.

5.2. Pharmacokinetic properties

A release membrane controls the transdermal delivery of fentanyl. Transdermal diffusion occurs at a relatively even speed for 72 hours following the application of the transdermal patch.

Absorption

After the first application of fentanyl transdermal patches, 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 dependent on the fentanyl transdermal patch size. For all practical purposes by 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.

Distribution

The plasma protein binding for fentanyl is 84%.

Biotransformation

Fentanyl is metabolised primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.

Elimination

When treatment with fentanyl transdermal patches is withdrawn, serum fentanyl concentrations decline gradually, falling approximately 50% in 13-22 hours in adults or 22-25 hours in children, respectively. Continued absorption of fentanyl from the skin accounts for a slower reduction in serum concentration than is seen after an intravenous infusion.

Around 75% of fentanyl is excreted into the urine, mostly as metabolites, with less than 10% as unchanged active substance. About 9% of the dose is recovered in the faeces, primarily as metabolites.

Pharmacokinetics in special populations

Older people

Data from intravenous studies with fentanyl suggest that older patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the active substance than younger patients. In a study conducted with a fentanyl transdermal patch, healthy older 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. Older patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.2).

Paediatric population

Adjusting for body weight, clearance (L/hour/Kg) in paediatric patients appears to be higher in children 2 to 5 years old and 25% higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are likely to have the same clearance as These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.

Hepatic impairment

In a study conducted with patients with hepatic cirrhosis, the pharmacokinetics of a single 50 microgram/hour application 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 Tilofyl reduced if necessary (see section 4.4).

Renal impairment

Data obtained from a study administering intravenious 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 Tilofyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.4).

5.3. Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.

In a rat study fentanyl did not influence male fertility. Studies with female rats revealed reduced fertility and enhanced embryonal mortality. More recent studies showed that effects on the embryo were due to maternal toxicity and not to direct effects of the substance on the developing embryo. There were no indications for teratogenic effects in studies in two species. In a study on pre- and postnatal development the survival rate of offspring was significantly reduced at doses which slightly reduced maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl on the pups. Effects on somatic development and behaviour of the offspring were not observed.

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumours at subcutaneous doses up to 33 microgram/kg/day in males or 100 microgram/kg/day in females. The overall exposure (AUC_{0-24 h}) achieved in this study was <40% of that likely to be achieved clinically at the dose strength of 100 microgram/hour Tilofyl transdermal patch, due to the maximum tolerated plasma concentrations in rats.

6.    PHARMACEUTICAL PARTICULARS

6.1.    List of excipients

Occlusive backing: polyethylene-terephthalate/ethylenvinylacetate-copolymer Drug reservoir: ethanol 96 %

hydroxyethylcellulose purified water

Release membrane: ethylenvinylacetate-copolymer Adhesive surface: silicone medical adhesive

Protective layer (remove before patch application): polyethylene-terephthalate, release coated

6.2. Incompatibilities

Not applicable

6.3    Shelflife

3 years

6.4.    Special precautions for storage

Store in the original package. Do not refrigerate or freeze.

6.5. Nature and contents of container

The transdermal patch is individually packaged in a protective sachet foil paper/PE/Al/PE. Packages containing 3, 5, 7, 10, 14 and 20 transdermal patches Not all pack sizes may be marketed.

Please refer to section 4.2 for instructions on how to apply the patch. There are no safety and pharmacokinetic data available for other application sites.

Significant quantities of fentanyl remain in the transdermal patches even after use. After removal, the used transdermal patches should be folded in half, adhesive side inwards so that the adhesive is not exposed, placed in the original sachet and then discarded safely out of the sight and reach of children. Unused patches should be returned to the pharmacy.

Wash hands with water only after applying or removing the patch.

7.    MARKETING AUTHORIZATION HOLDER

Tillomed Laboratories Limited

3 Howard Road

Eaton Socon

St. Neots

Cambs PE19 8ET

UK

8.    MARKETING AUTHORIZATION NUMBER

PL 11311/0311

9.    DATE OF FIRST AUTHORIZATION / RENEWAL OF THE

AUTHORIZATION

Date of first authorisation:28/07/2005 Date of latest renewal:5/07/2009

10 DATE OF REVISION OF THE TEXT

08/05/2015

1

Based on single-dose studies in which the i.m. dose of each above-mentioned agent was compared with morphine to establish the relative potency. Oral doses are those recommended when changing from a parenteral to an oral route.