SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Yemex 50 microgram/hour transdermal patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

2

One transdermal patch (21 cm absorption surface area) contains 11.56 mg fentanyl equivalent to a release rate of the active substance of 50 microgram/hour.

Excipient: Soya-bean oil, refined

Yemex 50 microgram/hour transdermal patch: 11.56 mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Transdermal patch

Transparent rounded oblong transdermal patch, consisting of a protective film (to be removed prior to application of the patch) and two functional layers: one self-adhesive matrix layer containing fentanyl and a carrier film impermeable to water.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Adults:

Severe chronic pain which can be adequately managed only with opioid analgesics 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

Yemex transdermal patches release fentanyl over 72 hours. The fentanyl release rate is 50 microgram/hour and the corresponding active surface area is 21 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 Yemex transdermal patches 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 12.5-25 microgram/hour.

Clinical experience with Yemex transdermal patches is limited in opioid-naive patients. In the circumstances in which therapy with Yemex transdermal patches 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) initially.

Patches with a release rate of 12.5 micrograms/hour are available and should be used for initial dosing. Patients can then be converted to Yemex transdermal patches 25 microgram/hour. The dose may subsequently be titrated upwards or downwards, if required, in increments of 12.5 or 25 micrograms/hour to achieve the lowest appropriate dose of Yemex transdermal patches depending on the response and supplementary analgesic requirements (see also section 4.4).

In treatment naive older or weak patients, it is not recommended to initiate an opioid treatment with Yemex 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 Yemex transdermal patches after determination of the optimal dosage.

Switching from other opioids

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.

Oral

30-40 (assuming repeated dosing) 7.5 20 30 4

10 (rectal)

60

200

0.8 (sublingual)

20-30

* 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.

Table 2: Recommended initial dose of Yemex transdermal based on daily oral morphine dose

(for patients who have a need for opioid rotation)

For adults

<90    12.5

90-134    25

135-179    37.5

180-224    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 dose of transdermal fentanyl based on daily oral morphine dose

(for patients on stable and well tolerated opioid therapy)

Oral    Transdermal

morphine dose    fentanyl release

(mg/24 h)    (micrograms/h)

<60    12.5

60-89    25

90-119    37.5

120-149    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

Previous analgesic therapy should be phased out gradually from the time of the first patch application until analgesic efficacy with Yemex transdermal patch is attained.

For both strong opioid-naive and opioid tolerant patients, the initial evaluation of the maximum analgesic effect of Yemex transdermal patch should not be made until the patch has been worn for 24 hours. This is due to the gradual increase in serum fentanyl concentrations during the first 24 hours after application of the patch.

By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/h can be achieved.

Dose titration and maintenance therapy

The Yemex 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 Yemex 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 after 3 days, until the desired effect is obtained for each patient. Dose adjustment, when necessary, should normally be performed in 12.5 microgram/hour or 25 microgram/hour increments, although the supplementary analgesic requirements (oral morphine 90 mg/day Yemex transdermal patch 25 micrograms/h) and pain status of the patient should be taken into account. More than one Yemex 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.

Changing or ending therapy

If discontinuation of Yemex transdermal patch 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 Yemex transdermal patch 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 Yemex transdermal patch to other therapies to avoid overestimating the new analgesic dose and potentially causing overdose.

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

Yemex transdermal patch should not be used in children under 2 years of age.

Children aged 16 years and above:

Follow adult dosage

Children aged 2 to 16 years old:

Yemex transdermal patch should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day. To convert paediatric patients from oral or parenteral opioids to Yemex transdermal patch, refer to Table 4.

Table 4: Recommended transdermal patch dose based upon daily oral morphine dose^{1 2}

Oral morphine dose    Transdermal fentanyl release

(mg/24 h)    ^(micr°g^rams/h)

For paediatric patients³

to Yemex transdermal patch. The conversion schedule should not be used to convert from Yemex transdermal patch into other opioids, as overdosing could then occur.

The analgesic effect of the first dose of Yemex transdermal patch will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Yemex transdermal patch, 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 Yemex transdermal patch therapy or up-titration of the dose (see also section 4.4).

Dose titration and maintenance

If the analgesic effect of Yemex transdermal patch 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 Yemex. Dose adjustments should be done in 12 microgram/hour steps.

Hepatic and renal impairment

Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).

Febrile patients

Patients with fever should be monitored for opioid side effects and the Yemex transdermal patch dose should be adjusted if necessary (see section 4.4).

Method of administration For transdermal use.

Directly after removal from the pack and the release liner, the Yemex transdermal patch is applied on the upper body (chest, back, 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.

Prior to application, the skin should be carefully washed with clean 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. The transdermal patch is then applied using slight pressure with the palm of the hand for approximately 30 seconds. The skin area to which the patch is applied should be free of microlesions (e.g. due to irradiation or shaving) and skin irritation.

As the transdermal patch is protected by an outer waterproof backing film, it can also be worn while showering.

If progressive dose increases are made, the active surface area required may reach a point where no further increase is possible.

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, colophonium resin (hydrogenated), soya, peanuts 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

-    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 Yemex transdermal patch 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.

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

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.

The transdermal patch should not be cut, since no information is available on the quality, efficacy and safety of such divided patches.

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 Yemex transdermal patch; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the Yemextransdermal patch. The incidence of respiratory depression increases as the fentanyl dose is

increased (see also section 4.9). CNS active substances may increase the respiratory depression (see section 4.5).

Opioid-naive and not opioid-tolerant states

Use of fentanyl transdermal patch in the opioid-naive patient has been associated with very rare cases of significant respiratory depression and/or fatality when used as initial opioid therapy. The potential for serious or life-threatening hypoventilation exists even if the lowest dosage 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:

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

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. Yemex can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Yemex 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 tntracranial pressure:

Yemex 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. Yemex transdermal patches should be used with caution in patients with brain tumors.

Cardiac disease:

Yemex 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 Yemex 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 Yemex transdermal patch, they should be observed carefully for signs of fentanyl toxicity and the dose of Yemex transdermal patch 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 kidney. If patients with renal impairment receive Yemex transdermal patch, 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 Yemex 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 Cmax values by 61%.

All patients should be advised to avoid exposing the Yemex transdermal patch application site to direct external heat sources such as heating pads, hot water bottles, electric blankets, heated water beds, heat or tanning lamps, intensive sunbathing, prolonged hot baths, saunas and hot whirlpool spa baths.

Serotonin syndrome

Caution is advised when Yemex 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 Reuptake 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 Yemex transdermal patches should be considered.

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 non-patch 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 substances than younger patients. If older patients receive Yemex transdermal patch, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).

PaediatricpopulationYemex 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 Yemex transdermal system administered.

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

To guard against accidental ingestion by children, caution should be used when choosing the application site for Yemex transdermal patch (see sSection 4.2) and the adhesion of the patch monitored 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 Yemex transdermal patch 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

The concomitant use of other central nervous system depressants, including opioids, sedatives, anxiolytics, hypnotics, general anesthetics, phenothiazines, tranquilizers, antipsychotics, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages, may produce additive depressant effects; hypoventilation, hypotension, and profound sedation, coma or death may occur. Therefore, the use of any of the above mentioned concomitant medicinal products requires special patient care and observation.

CYP3A4 inhibitors

Yemex, 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, 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 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):

Yemex 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, Yemex transdermal patch should not be used within 14 days after discontinuation of treatment with MAOIs. Serotonergic medicinal products

Coadministration of transdermal Yemex 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 (see also Section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Yemex 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. Yemex transdermal patch should not be used during pregnancy unless clearly necessary.

Use of Yemex transdermal patch during childbirth is not recommended because it should not be used in the management of acute or postoperative pain (see section 4.4). Moreover, because fentanyl passes through the placenta, the use of Yemex transdermal patch 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 Yemex transdermal patch and for at least 72 hours after removal of the patch.

4.7 Effects on ability to drive and use machines

Yemex transdermal patch may impair the mental and/or physical ability required to perform potentially hazardous tasks such as driving a car or operating machinery. Patients stabilised 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

Not known (cannot be estimated from the available data)_

Disorders
Cardiac Disorders		Palpitations, Tachycardia	Bradycardia, Cyanosis	Arrhythmi a
Vascular Disorders		Hypertensio n	Hypotension	Vasodilati on
Respiratory , Thoracic and Mediastinal Disorders		Dyspnoea,	Respiratory depression, Respiratory distress	Apnoea, Hypoventi lation	Bradypnoe a
Gastrointes tinal Disorders	Nausea1, Vomiting1 Constipati on1	Diarrhoea1, Dry mouth, Abdominal pain, Upper abdominal pain, Dyspepsia	Ileus	Subileus
Skin and Subcutaneo us Tissue Disorders		Hyperhidro sis, Pruritus1, Rash, Erythema	Eczema, Allergic dermatitis, Skin disorder, Dermatitis, Contact dermatitis
Musculoske letal and Connective Tissue Disorders		Muscle spasms	Muscle twitching
Renal and Urinary Disorders		Urinary retention
Reproducti ve System and Breast Disorders			Erectile dysfunction, Sexual dysfunction
General Disorders and Administrat ion Site Conditions		Fatigue, Peripheral oedema Asthenia, Malaise, Feeling cold	Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitiv	Applicatio n site dermatitis Applicatio n site eczema

Drug withdrawal syndrome2, Pyrexia

1    see “paediatric subjects” below

2    see “description of selected adverse reactions” below

As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can develop on repeated use of Yemex transdermal patch (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 Yemex 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 fentany patches during pregnancy (see section 4.6).

In very rare cases, soya-bean oil, refined can cause allergic reactions.

Paediatric population

The adverse event profile in children and adolescents treated with fentanyl transdermal patches 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 patches 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, diarrhea 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: www.mhra.gov.uk/yellowcard

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 Yemex 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, hypervolemia 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

Yemex 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

Following administration of Yemex transdermal patch, fentanyl is continuously absorbed through the skin over a period of 72 hours. Due to the polymer matrix and the diffusion of fentanyl through the skin layers, the release rate remains relatively constant.

Absorption

After the first application of Yemex 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 dependant on the Yemex transdermal patch size. For all practical purposesby 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

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

Elimination

When treatment with Yemex 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 Yemex 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 82% 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 adults. 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 Yemex transdermal patch 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 Yemex transdermal patch, 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 (AUC0-24 h) achieved in this study was <40% of that likely to be achieved clinically at the dose strength of 100 microgram/hour fentanyl transdermal patch, due to the maximum tolerated plasma concentrations in rats.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Protective film:

Poly(ethylene terephthalate) foil, siliconised

Self-adhesive matrix layer:

Colophonium resin (hydrogenated)

Poly(2-ethylhexyl acrylate-co-vinyl acetate)

Soya-bean oil, refined

Water-impermeable cover film: Poly(ethylene terephthalate)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years

6.4    Special precautions for storage

Store in the original package.

6.5    Nature and contents of container

The transdermal patches are individually packed in sachets made of paper/PE/Al/PE. Packs with 3, 5, 7, 10, 14, 16 and 20 transdermal patches.

Hospital packs with 5 transdermal patches.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal and other handling

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. Used transdermal patches should be folded with the adhesive surfaces inwards , so that the adhesive is not exposed, and then discarded safely and out of the reach of children and in accordance with local requirements. Any unused medicinal product should be discarded safely or returned to the pharmacy.

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

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04416/0825

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/04/2011

10 DATE OF REVISION OF THE TEXT

15/08/2014

1

30 - 44    12.5

45 - 134    25

2

   In clinical trials these ranges of daily oral morphine doses were used as a basis for

conversion to fentanyl transdermal patches

3

   Conversion to Yemex transdermal patch 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 Yemex 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)