SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Victanyl 12 micrograms/hour Transdermal Patch

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Victanyl 12 micrograms/h transdermal patch

Each patch releases 12.5 micrograms fentanyl per hour. Each patch of 4.25 cm² contains 2.55 mg fentanyl.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Transdermal patch

Each patch: Opaque and colourless rectangular shaped patch with round corners and imprint on the backing foil:

“Fentanyl 12^g/h”.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Adults:

The product is indicated

•    in the management of chronic intractable pain due to cancer.

•    in the management of chronic intractable pain.

Children:

The product is indicated for long term management of severe chronic pain in children receiving opioid therapy from 2 years of age.

4.2 Posology and method of administration

Posology

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

Initial dose selection

The appropriate initiating dose of Victanyl should be based on the patient's current opioid use. It is recommended that Victanyl be used in patients who have demonstrated opioid tolerance. Other factors to be considered are the current general condition and medical status of the patient, including body size, age, and extent of debilitation as well as degree of opioid tolerance.

Adults:

Opioid-tolerant patients

To convert opioid-tolerant patients from oral or parenteral opioids to Victanyl refer to Equianalgesicpotency conversion below. The dosage may subsequently be titrated upwards or downwards, if required, in increments of either 12 or 25 mcg/hr to achieve the lowest appropriate dose of Victanyl depending on response and supplementary analgesic requirements.

Opioid-naive patients

In strong opioid-naive patients, the normal initial Victanyl dosage should not exceed 25 mcg/h.

Clinical experience with Victanyl is limited in opioid-naive patients. In the circumstances in which therapy with Victanyl 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, hydromorphone, oxycodone, tramadol, and codeine) to attain equianalgesic dosage relative to Victanyl with a release rate of 25 mcg/hr. Patients can then be converted to Victanyl 25 mcg/hr. The dose may subsequently be titrated upwards or downwards, if required, in increments of 12 or 25 mcg/hr to achieve the lowest appropriate dose of Victanyl depending on the response and supplementary analgesic requirements (see also section 4.4 Special warnings and precautions for use: Opioid naive and not opioid-tolerant states).

Equianalgesic potency conversion

1.    Calculate the previous 24-hour analgesic requirement.

2.    Convert this amount to the equianalgesic oral morphine dose using Table 1. All IM and oral doses in this chart are considered equivalent to 10 mg of IM morphine in analgesic effect.

3. To derive the dosage of Victanyl corresponding to the calculated 24-hour, equianalgesic morphine dosage, use the dosage-conversion Table 2 or Table 3 as follows:

Table 2 is for adult patients who have been stabilised on oral morphine or another immediate-release opioid over several weeks and who need opioid rotation (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 150:1).

Table 3 is for highly opioid-tolerant adult patients who have been on a stable and well-tolerated opioid regimen for a long period, and who need opioid rotation (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 100:1).

Tables 2 and 3 should not be used to switch from transdermal fentanyl to another opioid treatment.

Table 1 Equianalgesic potency conversion

Drug name	Equianalgesic dose (mg)
	IM*	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

* Based on single-dose studies in which an IM dose of each drug listed was compared with morphine to establish the relative potency. Oral doses are those recommended when changing from a parenteral to an oral route.

** The oral/IM potency for morphine is based on clinical experience in patients with chronic pain.

Reference: Adapted from Foley KM. The treatment of cancer pain. NEJM 1985; 313 (2): 84-95, with updates.

Table 2: Recommended starting dosage of Victanyl based upon daily oral morphine dosage¹ (for patients stabilised on oral morphine or immediate release opioid for several weeks and who need opioid rotation)

Oral 24-hour morphine (mg/day)	Victanyl Dosage (mcg/hr)
< 44	12.5

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

¹ In clinical trials these ranges of daily oral morphine dosages were used as a basis for conversion to Victanyl.

Table 3: Recommended starting dosage of Victanyl based upon daily oral morphine dosage (for patients on stable and well tolerated opioid therapy for long periods and who need opioid rotation)

Oral 24-hour morphine (mg/day)	Victanyl Dosage (mcg/hr)
< 44	12.5
45-89	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

Previous analgesic therapy should be phased out gradually from the time of the first patch application until analgesic efficacy with Victanyl is attained. For both strong opioid-naive and opioid tolerant patients, the initial evaluation of the analgesic effect of Victanyl 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 Victanyl patch should be replaced every 72 hours. The dose should be titrated individually until a balance between analgesic efficacy and tolerability is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of fentanyl after 48 hours may be necessary. If analgesia is insufficient at the end of the initial application period, the dose may be increased. Dose adjustment, when necessary, should normally be performed in the following titration steps from 25 mcg/hr up to 75 mcg/hr: 25 mcg/hr, 37 mcg/hr, 50 mcg/hr, 62 mcg/hr and 75 mcg/hr; thereafter dose adjustments should normally be performed in 25 mcg/hr increments, although the supplementary analgesic requirements (oral morphine 90 mg/day ~ Victanyl 25 mcg/hr) and pain status of the patient should be taken into account. More than one Victanyl 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 Victanyl dose exceeds 300 mcg/hr.

Discontinuation of Victanyl

If discontinuation of Victanyl is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl concentrations fall gradually after Victanyl is removed, it takes 17 hours or more for the fentanyl serum concentrations to decrease 50% (see Section 5.2, Pharmacokinetic Properties). 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, Undesirable effects) are possible in some patients after conversion or dose adjustment.

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

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 drug than younger patients. Elderly, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2 Pharmacokinetic properties).

Use in patients with hepatic or renal impairment

Patients with impaired hepatic or renal function should carefully be observed for symptoms of an overdosage and the dose should possibly be reduced (see section 4.4).

Paediatric population

Children aged 16 years and above: follow adult dosage

Children aged 2 to 16 years old:

Victanyl 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 Victanyl refer to Table 1 “Equianalgesic potency conversion” and Table 4, “Recommended Victanyl dose based upon daily oral morphine dose”.

Table 4: Recommended Victanyl dose based upon daily oral morphine dose

Oral 24-Hour Morphine (mg/day)	Victanyl (mcg/hr)
For paediatric patients2
30 - 44	12
45 - 134	25

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

² Conversion to Victanyl doses greater than 25 mcg/hr 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 Victanyl 12 patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to Victanyl patches. The conversion schedule should not be used to convert from Victanyl into other opioids, as overdosing could then occur.

The analgesic effect of the first dose of Victanyl patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Victanyl, 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 patient for adverse events, which may include hypoventilation, is recommended for at least 48 hours after initiation of Victanyl therapy or up-titration of the dose (see also section 4.4, Special warnings and precautions for use).

Dose titration and maintenance

If the analgesic effect of Victanyl 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. Dose adjustments should be done in 12 mcg/hr steps.

Method of administration

For transdermal use.

Victanyl should be applied to non-irritated and non-irradiated skin on a flat surface or the torso or upper arm.

For use in children:

In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.

There are no safety and pharmacokinetic data available for other application sites.

All patients:

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 Victanyl 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 pouch should only be opened immediately before use of the transdermal patch and then the patch should be applied immediately after it is removed from the package and the release film and both sections of the backing film have been detached. 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.

Victanyl 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.

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

Occasionally, additional adhesion of the patch may be required.

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

If traces of the transdermal patch remain on the skin after its removal, these can be cleaned off using copious amounts of soap and water. No alcohol or other solvents may 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, 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.

-    Severe respiratory depression

4.4 Special warnings and precautions for use

FENTANYL SHOULD NOT BE USED IN THE MANAGEMENT OF ACUTE OR POSTOPERATIVE PAIN SINCE THERE IS NO OPPORTUNITY FOR DOSE TITRATION DURING SHORT-TERM USE AND BECAUSE SERIOUS OR LIFE-THREATENING HYPOVENTILATION COULD RESULT.

PATIENTS WHO HAVE EXPERIENCED SERIOUS ADVERSE EVENTS SHOULD BE MONITORED FOR AT LEAST 24 HOURS AFTER FENTANYL REMOVAL OR MORE AS CLINICAL SY,PTOMS DICTATE, BECAUSE SERUM FENTANYL CONCENTRATIONS DECLINE GRADUALLY AND ARE REDUCED BY ABOUT 50% 17 (RANGE 13-22) HOURS LATER.

Victanyl should be kept out of reach and sight of children at all times before and after use.

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

Use of Victanyl 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 Victanyl is used in initiating therapy in opioid-naive patients. It is recommended that Victanyl be used in patients who have demonstrated opioid tolerance (See Section 4.2, Posology and method of administration).

When Victanyl is administered for chronic intractable pain that will require prolonged treatment, it is strongly recommended that the physician defines treatment outcomes with regards to pain relief and functional improvement in accordance with locally defined pain management guidelines. Physician and patient should agree to discontinue treatment if these objectives are not met.

Respiratory depression

As with all potent opioids, some patients may experience significant respiratory depression with Victanyl; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the Victanyl patch. The incidence of respiratory depression increases as the Victanyl dose is increased (see Section 4.9, Overdose). CNS active drugs may increase the respiratory depression (see section 4.5, Interaction with other medicinal products and other forms of interaction).

Serotonin Syndrome

Caution is advised when Victanyl is coadministered with drugs that affect the serotonergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.

Serotonin syndrome may include mental-status changes (e.g., agitation, 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 Victanyl should be considered.

Interactions with other Medicinal Products:

Interactions with CYP3A4 Inhibitors

The concomitant use of Victanyl with cytochrome P450 3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole, 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 cytochrome P450 3A4 inhibitors is not recommended unless the patient is closely monitored. Patients, especially those who are receiving Victanyl and CYP3A4 inhibitors, should be monitored for signs of respiratory depression and dosage adjustments should be made if warranted.

Concomitant use of mixed agonists/antagonists

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see also Section 4.5, Interaction with other medicinal products and other forms of interaction).

Chronic pulmonary disease

Fentanyl, like other opioids, may have more severe adverse effects in patients with chronic obstructive or other pulmonary disease. In such patients, opioidsmay 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 such as fentanyl. Iatrogenic addiction following opioid administration is rare. 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. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Victanyl may result in overdose and/or death.

Increased intracranial pressure

Victanyl 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. Victanyl should be used with caution in patients with brain tumours.

Cardiac disease

Fentanyl may produce bradycardia and Victanyl 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 inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Victanyl, they should be observed carefully for signs of fentanyl toxicity and the dose of Victanyl reduced if necessary (see section 5.2 Pharmacokinetic properties).

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 Victanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2 Pharmacokinetic properties).

Patients with fever/external heat

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 Victanyl 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 Victanyl transdermal system increased mean fentanyl AUC values by 120% and mean Cmax values by 61%.

All patients should be advised to avoid exposing the Victanyl application site to direct external heat sources such as heating pads, hot water bottles, electric blankets, heated water beds, heat or tanning lamps, intensive sun bathing, prolonged hot baths, saunas or hot whirlpool spa baths while wearing the patch, since there is potential for temperature dependent increases in release of fentanyl from the patch.

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 in close physical contact with a patch wearer, may result in an opioid overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs, the transferred patch must be removed immediately from the skin of the non-patch wearer. (See Section 4.9, Overdose).

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 drug than younger patients. If elderly patients receive Victanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 5.2, Pharmacokinetic properties).

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 to take measures to prevent constipation and prophylactic laxative use may be considered in some situations. Extra caution should be used in patients with chronic constipation. If paralytic ileus is present or suspected, treatment with Victanyl should be stopped.

Use in paediatric patients

Victanyl should not be administered to opioid-naive paediatric patients (see section 4.2, Posology and method of administration). The potential for serious or life-threatening hypoventilation exists regardless of the dose of Victanyl administered

(see Table 2 in section 4.2, Posology and method of administration).

Victanyl has not been studied in children under 2 years of age and so should not be used in these children. Victanyl should be administered only to opioid-tolerant children age 2 years or older (see section 4.2, Posology and method of administration).

To guard against accidental ingestion by children, use caution when choosing the application site for Victanyl (see section 4.2, Posology and method of administration) and monitor adhesion of the patch closely.

Patch disposal

Used patches may contain significant residues of active substance. After removal, therefore, used patches should be folded firmly in half, adhesive side inwards, so that the adhesive is not exposed, and then discarded safely and out of the sight and reach of children according to the instructions in the pack.

As fentanyl is excreted into breast milk, breastfeeding should be discontinued during treatment with Victanyl (see also Section 4.6, Pregnancy and lactation).

Patients with myasthenia gravis

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

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 anesthetics, 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 drugs concomitantly with Victanyl requires special patient care and observation.

Fentanyl, a high clearance drug, 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 (See also section 4.4.).

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.

Serotoninergic Drugs

Co-administration of fentanyl with a serotoninergic 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.

Monoamine Oxidase Inhibitors (MAOI):

Victanyl 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. MAO-inhibitors have been reported to increase the effect of narcotic analgesics, especially in patients with cardiac failure. Therefore, fentanyl 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 (see also Section 4.4). The concomitant use of barbituric acid derivatives should be avoided, since the respiratory depressing effect of fentanyl may be increased.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have shown 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. Fentanyl should only be used during pregnancy when clearly necessary.

Use of fentanyl during labour and delivery (including caesarean section) is not recommended because it should not be used in the management of acute or postoperative pain, and because fentanyl passes the placenta and may cause respiratory depression in the fetus or in the infant (see section 4.3).

Breast-feeding

Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breast-fed infant. Breast feeding should therefore be discontinued during treatment and for at least 72 hours after the removal of Victanyl (see also section 4.4).

Fertility

There are no human data on fertility available. Animal studies have shown reduced fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Victanyl may impair the mental and/or physical ability required to perform potentially hazardous tasks such as driving a car or operating machinery.

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:

-    The medicine has been prescribed to treat a medical or dental problem and

-    You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

-    It was not affecting your ability to drive safely

4.8 Undesirable effects

The safety of fentanyl was evaluated in 1854 subjects who participated in 11 clinical trials (double-blind fentanyl [placebo or active control] and/or open label fentanyl [no control or active control]) used for the management of chronic malignant or nonmalignant pain. These subjects took at least 1 dose of fentanyl 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 ADRs reported with the use of fentanyl from these clinical trials, including the above-mentioned ADRs, and from post-marketing experiences are listed below in Table A.

The following frequencies are used for the description of the occurrence of adverse reactions:

Very common: (>1/10)

Common: (>1/100, <1/10)

Uncommon: (>1/1000 to <1/100)

Rare: (>1/10,000 to <1/1000)

Very rare: (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

The most serious undesirable effect of fentanyl is respiratory depression.

Table A: Adverse Drug Reactions in Adult and Paediatric Subjects

System Organ Class	Adverse Drug Reactions
	Frequency Category
	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)	Not Known
Immune System Disorders		Hypersensitivity			Anaphylactic shock, Anaphylactic reaction, Anaphylactoi d reaction
Metabolism and Nutrition Disorders		Anorexia
Psychiatric Disorders	Insomnia, Somnolence	Depression, Anxiety, Confusional state, Hallucination	Agitation, Disorientation, Euphoric mood
Nervous System Disorders	Dizziness, Headache	Tremor, Paraesthesia	Hypoaesthesia, Convulsion (including clonic convulsions and grand mal convulsion), Amnesia Depressed level of consciousness, Loss of consciousness
Eye Disorders			Vision blurred	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, Hypo ventilation	Bradypnoea

Gastrointestinal Disorders	Nausea, Vomiting, Constipation	Diarrhoea, Dry mouth, Abdominal pain, Abdominal pain upper, Dyspepsia	Ileus	Subileus
Skin and Subcutaneous Tissue Disorders		Hyperhidrosis, Pruritus,Rash, Erythema	Eczema, Allergic dermatitis, Skin disorder, Dermatitis, Contact dermatitis
Musculoskeletal 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, Peripheral oedema, Asthenia, Malaise Feeling cold	Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivity, Drug withdrawal syndrome, Pyrexia	Application site dermatitis, Application site eczema

Other undesirable effects

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

Paediatric population

The adverse event profile in children and adolescents treated with Victanyl 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 Victanyl 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.

The safety of fentanyl was evaluated in 289 paediatric subjects (<18 years) who participated in 3 clinical trials for the management of chronic or continuous pain of malignant or non-malignant origin. These subjects took at least one dose of fentanyl and provided safety data. Although the enrolment criteria for the paediatric studies restricted enrolment to subjects who were a minimum of 2 years of age, 2 subjects in these studies received their first dose of fentanyl at an age of 23 months.

Based on pooled safety data from these 3 clinical trials in paediatric subjects, the most commonly reported (ie >10% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): vomiting (33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%). Table B displays all ADRs reported in fentanyl-treated paediatric subjects in the aforementioned clinical trials.

The ADRs for the paediatric population presented in Table B were assigned to frequency categories using the same conventions as used for Table A.

Table B: Adverse Drug Reactions in Paediatric Subjects in clinical trials

System Organ Class	Adverse Drug Reactions
	Frequency Category
	Very Common	Common	Uncommon
Immune System Disorders		Hypersensitivity
Metabolism and Nutrition Disorders		Anorexia
Psychiatric Disorders		Insomnia Somnolence, Anxiety, Depression, Hallucination	Confusional state
Nervous System Disorders	Headache	Dizziness, Tremor, Hypoaesthesia	Paraesthesia
Eye Disorders			Miosis
Ear and Labyrinth Disorders			Vertigo

Cardiac Disorders			Cyanosis
Respiratory, Thoracic and Mediastinal Disorders		Respiratory depression
Gastrointestinal Disorders	Vomiting, Nausea, Constipation, Diarrhoea	Abdominal pain, Upper abdominal pain, Dry mouth
Skin and Subcutaneous Tissue Disorders	Pruritus	Rash, Hyperhidrosis, Erythema	Contact dermatitis, Skin disorder, Allergic dermatitis, Eczema
Musculoskeletal and Connective Tissue Disorders		Muscle spasms
Renal and Urinary Disorders		Urinary retention
General Disorders and Administration Site Conditions		Peripheral oedema Fatigue, Application site reaction, Asthenia	Drug withdrawal syndrome, Influenza-like illness

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

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

Treatment

For management of respiratory depression immediate countermeasures should be started, including removing the patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone.

Respiratory depression following an overdose may outlast the duration of action of 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, if

required by the patient’s clinical condition. 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: opioids; Phenylpiperidine derivatives, ATC code: N02AB03

Paediatric population

The safety of fentanyl was evaluated in three open-label trials in 289 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 pg/h patch. Starting doses of 25 pg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg per dose of oral morphine.

5.2 Pharmacokinetic properties

Absorption

Victanyl 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 drug release. After the first Victanyl application, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours, and remaining relatively constant for the remainder of the 72-hour application period. The serum fentanyl concentrations attained are proportional to the Victanyl patch 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 has suggested that serum fentanyl concentrations may increase by 14% (range 0- 26%) if a new patch is applied after 24 hours rather than the recommended 72-hour application.

Distribution

The plasma protein binding for fentanyl is 84 %.

Biotransformation

Fentanyl is a high clearance drug 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 Victanyl 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 drug from the serum than is seen after an IV infusion, where the apparent halflife 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 drug. 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%.

Special populations

Elderly

Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the drug than younger patients. In a study conducted with Victanyl, healthy elderly subjects had fentanyl pharmacokinetics which did not differ significantly from healthy young subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.2 Posology and method of administration).

Paediatric Patients

Adjusting for body weight, clearance (L/hr/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 pg/hr application of Victanyl 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 Victanyl reduced if necessary (see section 4.4 Special warnings and precautions for use).

Renal impairment

Data obtained from a study administering IV fentanyl in patients undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population. If patients with renal impairment receive Victanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.4 Special warnings and precautions for use).

The transdermal patch is an application form for the systemic administration of fentanyl, which ensures that an adequate serum level of fentanyl will be maintained over a period of 72 hours with a constant rate of release.

The transdermal patch consists of two functional layers:

The topside consists of a waterproof backing film with a selfadhesive fentanyl-containing matrix layer on it. This matrix layer is covered by a removable foil which - due to slits - can be easily removed prior to use.

The 4.25 cm patch delivers approximately 12 micrograms/hour fentanyl to the skin. This is achieved by means of the polymer matrix: A concentration gradient is created between the polymer matrix with high concentrations of the active substance fentanyl and the skin with low concentration of fentanyl. Over a period of 72 hours fentanyl diffuses towards the lower concentration, i.e. towards the skin.

The relative bioavailability of fentanyl from the patch is 92%. The serum fentanyl concentrations attained are proportional to the patch size.

Preclinical safety data

In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation. Fentanyl showed no evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays.

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 pg/kg/day in males or 100 pg/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 highest dose strength of Victanyl, 100 mcg/h, due to the maximum tolerated plasma concentrations in rats.

Fentanyl was assessed for effects on fetal development in the rat and rabbit. Some tests on female rats showed reduced fertility as well as embryo mortality and transient development delays. These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo. These changes were observed at steady-state plasma concentrations equivalent to (C_ss, _rat / C_ss,    = 1.1) and daily exposures

slightly greater (AUC_0-24, _rat / AUC_0-24, _human = 1.5) than those observed in the clinic following use of the 100 mcg/h patch. No effects were observed in the rabbit, where a maximum plasma concentration 6.6-fold the human steady-state fentanyl plasma concentration was achieved. The daily exposure ratio (AUC_4-24, _rabbit / AUC_0-24, _human = 1.1) was equivalent to those observed in the clinic following use of the 100 mcg/h patch. There was no evidence of teratogenic effects.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Matrix Components:

Aloe vera leaf extract oil (on the basis of soya oil tocopherol acetate) Pentaerythriol esters of hydrogenated colophony Poly(2-ethylhexylacrylate,vinylacetate) (50:50)

Release liner:

Polyethylene terephtalat, polyester, siliconized

Backing foil with imprint:

Polyethylene terephthalat foil,

Blue printing colour

Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

6.4    Special precautions for    storage

This medicinal product does not require any special storage conditions.

Only open the pouch immediately before use of the patch.

6.5    Nature and contents of    container

Each transdermal patch is packed individually into a sealed child resistant pouch. The pouch is composed of Polyflex foil (a laminate foil made up of, PET, aluminium foil and a Surlyn heat-sealable layer) and is tightly sealed.

5, 10, 16, 20 transdermal patches

Not all pack sizes may be marketed.

6.6    Special precautions for    disposal

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.

High quantities of fentanyl remain in the transdermal patches even after use. Used patches should be folded so that the adhesive side of the patch adheres to itself and

then they should be safely discarded out of the reach of children. Unused patches should be returned to the (hospital) pharmacy.

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

7    MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0637

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/08/2015

10    DATE OF REVISION OF THE TEXT

30/10/2015