SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Mylafent 100 microgram/hour Transdermal Patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Mylafent 100 microgram/hour transdermal patch contains 16.8 mg of fentanyl in a patch size 42.0 cm², releasing 100 micrograms of fentanyl per hour.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Transdermal patch

A translucent rectangular patch printed with white ink on a removable liner.

The following is printed on a patch:

Fentanyl 100 gg/h

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

Mylafent is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.

Children and adolescents:

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

4.2 Posology and method of administration

Posology

Adults:

The dosing is individual and based on the patient’s opioid history and takes in to account:

possible development of tolerance

the current general condition, the medical status of the patient, and the degree of severity of the disorder

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

Patients receiving opioid treatment for the first time

Patches with a release rate of 12 micrograms/hour are available and should be used for initial dosing. In very elderly or weak patients, it is not recommended to initiate a treatment with Mylafent 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 Mylafent 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:

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

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

The corresponding fentanyl dosage should be determined as follows: using Table 2 for patients who have a need for opioid rotation (conversion ratio of oral morphine to transdermal fentanyl equal to 150:1) using Table 3 for patients stable and well tolerated opioid therapy (conversion ratio of oral morphine to transdermal fentanyl equal to 100:1)

Table 1: Equianalgesic potency conversion

All dosages given in the table are equivalent in analgesic effect to 10 mg morphine._

Active Substance	Equianalgesic dosage (mg)
	Parentaral i.m	Oral
Morphine	10	30-40
Hydromorphone	1.5	7.5
Methadone	10	20
Oxycodone	10-15	20-30
Levorphanol	2	4
Oxymorphine	1	10 (rectal)
Diamorphine	5	60
Pethidine	75	-
Codeine	-	200
Buprenorphine	0.4	0.8 (sublingual)
Ketobemidone	10	20-30

Table 2: Recommended Mylafent dose based upon the oral daily

morphine

dose

Oral 24 hours morphine (mg/day)	Mylafent dose (dg/h)
30-44	12
45-134	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 Mylafent initial dosage based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)

Oral morphine dose (mg/24 h)	Mylafent release (pg/h)
< 60	12
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

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

The initial evaluation of the maximum analgesic effect of Mylafent should not be made before 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.

In the first 12 hours after changing to Mylafent the patient continues to receive the previous analgesic at the previous dose; over the next 12 hours this analgesic is administered according to need.

Dose titration and maintenance therapy

The patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of Mylafent after 48 hours may be necessary.

Patches with a release rate of 12 microgram/hour are available and are appropriate for dose titration in the lower dosage area. 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. Additional dose adjustment should normally be performed in 25 microgram/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account. Patients may require periodic supplemental doses of a short-acting analgesic for breakthrough pain. Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the fentanyl dose exceeds 300 microgram/hour.

Withdrawal symptoms have been reported when changing from long-term treatment with morphine to transdermal fentanyl despite adequate analgesic efficacy. In case of withdrawal symptoms it is recommended to treat those with short-acting morphine in low doses.

Change or discontinuation of therapy

If discontinuation of the patch is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl levels fall gradually after the patch is removed; it takes at least 17 hours for the fentanyl serum concentration to decrease by 50%.

As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety and muscular tremor). Tables 2 and 3 should not be used to switch from transdermal fentanyl to a morphine treatment.

Special Populations

Elderly patients:

Elderly should be observed carefully and the dose reduced if necessary (see sections 4.4 and 5.2).

Renal impairment:

Patients with impaired renal function should be observed carefully and the dose reduced if necessary (see section 4.4).

Hepatic impairment:

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

Paediatric population:

Adolescents aged 16 years and above: follow adult dosage Children and adolescents aged 2 to 16 years old:

Mylafent 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 opioids to Mylafent refer to Table 4 Recommended Mylafent dose based upon daily oral morphine dose.

Table 4: Recommended Mylafent based upon daily oral morphine dose¹

Oral 24-hour Morphine (mg/day)	Mylafent
For paediatric patients2
30-44	12
45-134	25

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

²Conversion to fentanyl doses greater than 25 pg/h is the same for adult and paediatric population

For children who received more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl dose was calculated conservatively: 30 mg to 44 mg oral morphine per day or its equivalent opioid dose was replaced by one Mylafent 12 microgram/hr patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to Mylafent product. The conversion schedule could not be used to convert from Mylafent into other opioids, as overdose could then occur.

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

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

Dose titration and maintenance

If the analgesic effect of Mylafent 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 use more patches. Dose adjustments should be done in 12 microgram/hour steps.

Method of administration

For transdermal use

Mylafent 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 application. If the site of Mylafent application requires to be cleansed prior to application of the patch, this should be done with water. Soaps, oils, lotions or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before the patch is applied. Patches should be inspected prior to use. Patches that are cut, divided, or damaged in any way should not be used.

The Mylafent should be removed from the protective sachet by making a small cut near the sealed edge of the sachet and then carefully tearing the sachet open by hand. Grasp both sides of the opened sachet and pull apart so that sachet is open on three sides, and remove the patch.

Mylafent should be applied immediately after removal from the sealed sachet. Avoid touching the adhesive side of the patch. Following removal of both parts of the protective liner, 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. Then wash hands with clean water.

Mylafent should be worn continuously for 72 hours. A new patch should then be applied to a different skin site after removal of the previous transdermal patch. Several days should elapse before a new patch is applied to the same area of skin.

The need for continued treatment should be assessed at regular intervals.

To prevent interference with the adhesive properties of the patch, no creams, oils, lotions or powder should be applied to the skin area when the patch is applied.

Do not cut Mylafent. A patch that has been divided, cut, or damaged in any way should not be used.

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 or life-threatening hypoventilation could result.

Severe impairment of the central nervous system.

4.4 Special warnings and precautions for use

Patients who have experienced serious adverse events should be monitored for up to 24 hours after Mylafent removal since serum fentanyl concentrations decline gradually and are reduced by about 50% 17 (range 13-22) hours later.

Respiratory depression:

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

Chronic pulmonary disease:

Mylafent 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.

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. Patients with a prior history of 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. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Mylafent may result in overdose and/or death.

Increased intracranial pressure:

Mylafent 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. Mylafent should be used with caution in patients with brain tumors.

Cardiac disease:

Fentanyl may produce 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 Mylafent is initiated.

Hepatic impairment:

Because fentanyl is metabolized to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Mylafent they should be observed carefully for signs of fentanyl toxicity and the dose of Mylafent 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 Mylafent, 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 undesirable effects and the Mylafent 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 Mylafent system increased mean fentanyl AUC values by 120% and mean C_max values by 61%.

All patients should be advised to avoid exposing the Mylafent 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.

Use in elderly patients

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 active substance than younger patients. If elderly patients receive Mylafent they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).

Use in paediatrics

Mylafent 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 Mylafent administered.

Mylafent was not studied in children under 2 years of age. Mylafent should be administered only to opioid-tolerant children age 2 years or older (see section 4.2). Mylafent 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 Mylafent (see section 6.6) and monitor adhesion of the patch closely.

Patients with myasthenia gravis

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

Accidental Exposure by Patch Transfer

Accidental transfer of a fentanyl patch to the skin of a non-patch wearer (particularly a child), while sharing a bed or being close physical contact with a patch wearer, may result in an opioid overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs, the transferred patch must be removed immediately from the skin of the non-patch wearer. (see section 4.9 Overdose)

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant use of other central nervous system depressants, including opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquilizers, 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 these active substances concomitantly with Mylafent requires special patient care and observation.

Fentanyl, a high clearance active substance, is rapidly and extensively metabolized 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.

Monoamine Oxidase Inhibitors (MAOI):

Mylafent 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, Mylafent should not be used within 14 days after discontinuation of treatment with MAOIs.

Concomitant use of mixed agonists/antagonists

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

4.6 Fertility, Pregnancy and lactation

There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown, although fentanyl as an IV anaesthetic has been found to cross the placenta in early human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl during pregnancy. Mylafent should not be used during pregnancy unless clearly necessary.

Use of Mylafent 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 Mylafent during childbirth might result in respiratory depression in the newborn infant.

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

4.7 Effects on ability to drive and use machines

Mylafent has major influence on the ability to drive and use machines. This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilisers. Patients stabilised on a specific dosage will not necessarily be restricted. Therefore, patients should consult their physician as to whether driving or use of machines is permitted.

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 following frequencies are used for the description of the occurrence of adverse reactions: 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 clinical trial data).

System Organ Class	Adverse Drug Reactions
	Frequency Category
	Very Common	Common	Uncommon	Rare	Not Known

System Organ Class	Adverse Drug Reactions
	Frequency Category
	Very Common	Common	Uncommon	Rare	Not Known
Immune System Disorders		Hypersensitivi ty			Anaphylacti c shock, Anaphylacti c reaction, Anaphylacto id reaction
Metabolism and Nutrition Disorders		Anorexia
Psychiatric Disorders		Insomnia, Depression, Anxiety, Confusional state, Hallucination	Agitation, Disorientation , Euphoric mood
Nervous System Disorders	Somnolence, Dizziness, Headache	Tremor, Paraesthesia	Hypoaesthesia , Convulsion (including clonic convulsions and grand mal convulsion), Amnesia
Eye Disorders				Miosis
Ear and Labyrinth Disorders		Vertigo
Cardiac Disorders		Palpitations, Tachycardia	Bradycardia, Cyanosis
Vascular Disorders		Hypertension	Hypotension
Respiratory, Thoracic and Mediastinal Disorders		Dyspnoea	Respiratory depression, Respiratory distress	Apnoea, Hypovent ilation	Bradypnoea,
Gastrointestinal Disorders	Nausea, Vomiting, Constipation	Diarrhoea, Dry mouth, Abdominal pain, Abdominal pain upper, Dyspepsia	Ileus	Subileus

System Organ Class	Adverse Drug Reactions
	Frequency Category
	Very Common	Common	Uncommon	Rare	Not Known
Skin and Subcutaneous Tissue Disorders		Hyperhidrosis , Pruritus, Rash, Erythema	Eczema, Dermatitis allergic, Skin disorder, Dermatitis, Dermatitis contact
Musculoskeleta l and Connective Tissue Disorders		Muscle spasms	Muscle twitching
Renal and Urinary Disorders		Urinary retention
Reproductive System and Breast Disorders			Erectile dysfunction, Sexual dysfunction
General Disorders and Administration Site Conditions		Fatigue, Oedema peripheral, Asthenia, Malaise, Feeling cold	Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivi ty, Active substance withdrawal syndrome	Applicati on site dermatitis 5 Applicati on site eczema

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

Paediatric Subjects

The adverse event profile in children and adolescents treated with fentanyl 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 use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, vomiting, and nausea.

4.9 Overdose

Symptoms

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

Treatment

For management of respiratory depression, immediate countermeasures include removing the Mylafent 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-narcotization 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, hypovolemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nervous system; analgesics; opioids; phenylpiperidine derivatives ATC Code: N02AB03

Fentanyl is an opioid analgesic with affinity mainly to the p-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 nanogram/ml; an increased incidence of adverse reactions is observed if serum levels exceed 2 nanogram/ml. Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. The tendency to develop tolerance varies considerably between individuals

5.2 Pharmacokinetic properties

Adults

Mylafent provides continuous systemic delivery of fentanyl over the 72 hour administration period. Fentanyl is released at a relatively constant rate. The concentration gradient existing between the matrix and the lower concentration in the skin drives active substance release

Absorption

After the first application of Mylafent, serum fentanyl concentrations increases gradually, generally levelling off between 12 and 24 hours, and remaining relatively constant for the remainder of the 72-hour application period. The serum fentanyl concentrations attained are proportional to the Mylafent size. 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.

A pharmacokinetic model suggested that fentanyl serum concentrations can increase 14% (range 0-26%), if a new patch is applied after 24 hours instead of 72 hours as recommended.

Distribution

The plasma protein binding for fentanyl is 84%.

Biotransformation

Fentanyl is a high clearance active substance and is rapidly and extensively metabolised primarily by CYP3A4 in the liver. The major metabolite, norfentanyl, is inactive. 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.

Elimination

After Mylafent 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 the skin accounts for a slower disappearance of the active substance from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12 hours). Fentanyl is metabolised primarily in the liver. Within 72 hours of IV fentanyl administration, approximately 75% of the fentanyl dose is excreted into the urine, mostly as metabolites, with less than 10% as unchanged active substance. About 9% of the dose is recovered in the faeces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

Pharmacokinetics in special groups

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.

Elderly and Debilitated Population

Elderly and debilitated patients may have reduced clearance of fentanyl leading to prolonged terminal half -life. In patients with renal or hepatic impairment, clearance of fentanyl may be altered because of changes of plasma proteins and metabolic clearance resulting in increased serum concentrations (see sections 4.2 and 4.4).

Hepatic impairment

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

Renal impairment

Data obtained from a study administering IV fentanyl in patients undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population. If patients with renal impairment receive Mylafent 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 and genotoxicity.

Animal studies have shown reduced fertility and increased mortality in rat foetuses. Tetratogenic effects have, however, not been demonstrated.

Long-term carcinogenicity studies have not been performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Adhesive layer Polyacrylate Adhesive

Backing layer

Polethylene terephthalate/ethyl vinyl acetate film White printing ink

Protective liner Siliconised Polyester Film

6.2 Incompatibilities

To prevent interference with the adhesive properties of the patch, no creams, oils, lotions or powder should be applied to the skin area when the patch is applied.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Each patch is packed in a heat-sealed sachet made of child resistant polyethylene terephthalate, white-pigmented low density polyethylene, aluminium foil, and low density polyethylene. Sachets are placed into a paperboard carton with a patient information leaflet.

Pack sizes: 3, 4, 5, 8, 10, 16, 20 transdermal patches Not all pack sizes may be marketed.

6.6    Special precautions for disposal

For environmental and safety reasons, used as well as unused and / or out of date patches must be discarded safely or returned to the pharmacy for disposal. High quantities of fentanyl remain in the transdermal patch even after use. Used patches should be folded so that the adhesive side of the patch adheres to itself and kept in the outer package until discarded safely or delivered to the pharmacy. Unused patches should be returned to the hospital pharmacy to be disposed of in accordance with the local requirements.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1365

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/04/2012

10 DATE OF REVISION OF THE TEXT

18/11/2014