Victanyl 100 micrograms/hour Transdermal Patch – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Victanyl 100 micrograms/hour Transdermal Patch

fentanyl

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each patch releases 100 micrograms fentanyl per hour. Each patch of 30 cm2 contains 16.5 mg fentanyl.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Transdermal patch

Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 100µg/h“.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults:

The product is indicated in 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

Treatment duration and goals

Prior to starting treatment with Victanyl patches, a discussion should be held with patients to put in place a treatment strategy including treatment duration and treatment goals, and a plan for ending treatment with fentanyl should be agreed together with the patient, in accordance with pain management guidelines, in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4). During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

Posology

Victanyl doses should be individualised based upon the status of the patient and should be assessed at regular intervals after application. The lowest effective dose should be used. The patches are designed to deliver approximately 25, 50, 75, and 100 mcg/h fentanyl to the systemic circulation, which represent about 0.6, 1.2, 1.8, and 2.4 mg per day respectively.

Initial dosage 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 Equianalgesic potency conversion below. The dosage may subsequently be titrated upwards or downwards, if required, in increments of either 12 or 25 mcg/h to achieve the lowest appropriate dosage of Victanyl depending on the response and supplementary analgesic requirements.

Opioid-naïve patients

Generally, the transdermal route is not recommended in opioid-naïve patients. Alternative routes of administration (oral, parenteral) should be considered. To prevent overdose it is recommended that opioid-naïve patients receive low doses of immediate release opioids (e.g. morphine, hydromorphone, oxycodone, tramadol and codeine) that are to be titrated until an analgesic dosage equivalent to transdermal fentanyl with a release rate of 12 mcg/h or 25 mcg/h is attained. Patients can then switch to Victanyl. Patches with a release rate of 12 mcg/h are available and should be used for initial dosing.

In the circumstance in which commencing with oral opioids is not considered possible and transdermal fentanyl is considered to be the only appropriate treatment option for opioid-naïve patients, only the lowest starting dose (i.e. 12 mcg/h) should be considered. In such circumstances, the patient must be closely monitored. The potential for serious or life-threatening hypoventilation exists even if the lowest dose of transdermal fentanyl is used in initiating therapy in opioid-naïve patients (see sections 4.4 and 4.9).

Equianalgesic potency conversion

In patients currently taking opioid analgesics, the starting dose of Victanyl should be based on the daily dose of the prior opioid. To calculate the appropriate starting dose of Victanyl, follow the steps below.

1. 1. Calculate the 24-hour dose (mg/day) of the opioid currently being used.
2. 2. Convert this amount to the equianalgesic 24-hour oral morphine dose using the multiplication factors in Table 1 for the appropriate route of administration.
3. 3.

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

   a.Table 2 is for adult patients who have a need for opioid rotation or who are less clinically stable (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 150:1). b. Table 3 is for adult patients who are on a stable, and well tolerated opioid regimen (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 100:1).

Table 1: Conversion Table - Multiplication Factors for Converting the Daily

Dose of Prior Opioids to the Equianalgesic 24-hour Oral Morphine Dose (mg/day Prior Opioid x Factor = Equianalgesic 24-hour Oral Morphine Dose)

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

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

Reference: Adapted from 1) Foley KM. The treatment of cancer pain. NEJM 1985; 313 (2): 84-95 and 2) McPherson ML. Introduction to opioid conversion calculations. In: Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. Bethesda, MD: American Society of Health-System Pharmacists; 2010:1-15.

Table 2: Recommended starting dosage of transdermal fentanyl based upon daily oral morphine dose (for patients who have a need for opioid rotation or for clinically less stable patients: conversion ratio of oral morphine to transdermal fentanyl is approximately equal to 150:1) 1 Oral 24-hour morphine,

(mg/day)

Transdermal fentanyl

Dosage

(mcg/h)

<90 12 90-134 25 135-224 50 225-314 75 315-404 100 405-494 125 495-584 150 585-674 175 675-764 200 765-854 225 855-944 250 945-1034 275 1035-1124 300 ¹ In clinical studies these ranges of daily oral morphine doses were used as a basis for conversion to transdermal fentanyl

Table 3: Recommended starting dosage of transdermal fentanyl based upon daily oral morphine dosage (for patients on stable and well tolerated opioid therapy: conversion ratio of oral morphine to transdermal fentanyl is approximately equal to 100:1)

Oral 24-hour morphine

(mg/day)

Transdermal fentanyl

Dosage

(mcg/h)

≤44 12 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

Initial evaluation of the maximum analgesic effect of Victanyl cannot be made before the patch is worn for 24 hours. This delay is due to the gradual increase in serum fentanyl concentration in the 24 hours following initial patch application.

Previous analgesic therapy should therefore be gradually phased out after the initial dose application until analgesic efficacy with Victanyl is attained.

Dose titration and maintenance therapy

The Victanyl patch should be replaced every 72 hours.

The dose should be titrated individually on the basis of average daily use of supplemental analgesics, until a balance between analgesic efficacy and tolerability is attained. Dosage titration should normally be performed in 12 mcg/h or 25 mcg/h increments, although the supplementary analgesic requirements (oral morphine 45/90 mg/day ≈ transdermal fentanyl 12/25 mcg/h) and pain status of the patient should be taken into account. After an increase in dose, it may take up to 6 days for the patient to reach equilibrium on the new dose level. Therefore after a dose increase, patients should wear the higher dose patch through two 72-hour applications before any further increase in dose level is made.

More than one Victanyl patch may be used for doses greater than 100 mcg/h. Patients may require periodic supplemental doses of a short-acting analgesic for “breakthrough” pain. Some patients may require additional or alternative methods of opioid administration when the Victanyl dose exceeds 300 mcg/h.

In the absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

If analgesia is insufficient during the first application only, the Victanyl patch may be replaced after 48 hours with a patch of the same dose, or the dose may be increased after 72 hours.

If the patch needs to be replaced (e.g. the patch falls off) before 72 hours, a patch of the same strength should be applied to a different skin site. This may result in increased serum concentrations (see section 5.2) and the patient should be monitored closely.

Discontinuation of Victanyl

If discontinuation of Victanyl is necessary, replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl concentrations fall gradually after transdermal fentanyl is removed. It may take 20 hours or more for the fentanyl serum concentrations to decrease 50%. In general, the discontinuation of opioid analgesia should be gradual in order to prevent withdrawal symptoms (see sections 4.4 and 4.8). There have been reports that rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms and uncontrolled pain. Tapering should be based on the individual dose, treatment duration and response of the patient regarding pain and withdrawal symptoms. Patients on long-term treatment may need a more gradual tapering. For patients who had been treated for a short period, a faster reduction schedule may be considered.

Opioid withdrawal symptoms are possible in some patients after conversion or dose adjustment.

Tables 1, 2, and 3 should only be used to convert from other opioids to transdermal fentanyl and not from transdermal fentanyl to other therapies to avoid overestimating the new analgesic dose and potentially causing overdose.

Special populations

Elderly patients

Elderly patients should be observed carefully and the dose should be individualised based upon the status of the patient (see sections 4.4 and 5.2). In opioid-naïve elderly patients, treatment should only be considered if the benefits outweigh the risks. In these cases, only transdermal fentanyl 12 mcg/h dosage should be considered for initial treatment.

Renal and hepatic impairment

Patients with renal or hepatic impairment should be observed carefully and the dose should be individualised based upon the status of the patient (see sections 4.4 and 5.2).

In opioid-naïve patients with renal or hepatic impairment, treatment should only be considered if the benefits outweigh the risks. In these cases, only transdermal fentanyl 12 mcg/h dosage should be considered for initial treatment.

Paediatric population

Children aged 16 years and above:

Follow adult dosage.

Children 2 to 16 years old:

Victanyl should be administered to only those 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 Victanyl refer to Equianalgesic potency conversion (Table 1) and Recommended Victanyl dosage based upon daily oral morphine dose (Table 4).

Table 4: Recommended transdermal fentanyl dosage for paediatric patients¹ based upon daily oral morphine dose²

Oral 24 hour morphine

(mg/day)

Transdermal Fentanyl dose

(mcg/h) 30-44 12 45-134 25 ¹ Conversion to fentanyl transdermal dosages greater than 25 mcg/h is the same for paediatric patients as it is for adult patients (see table 2). ² In clinical studies these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal patches.

In two 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 transdermal fentanyl 12 mcg/h patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to fentanyl patches. The conversion schedule should not be used to convert from transdermal fentanyl into other opioids, as overdosing could then occur.

The analgesic effect of the first dose of fentanyl 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.

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 section 4.4).

Victanyl should not be used in children aged less than 2 years because the safety and efficacy have not been established.

Dose titration and maintenance in children

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. Dosage must not be increased in intervals of less than 72 hours. 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/h steps.

Method of administration

Victanyl is for transdermal use.

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

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

Hair at the application site (a non-hairy area is preferable) should be clipped (not shaved) prior to application. If the site of Victanyl application requires cleansing prior to application of the patch, this should be done with clear 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.

Victanyl should be applied immediately upon removal from the sealed package. The patch should be removed from the protective pouch by first folding the notch (located close to the tip of the arrow on the pouch label) and then carefully tearing the pouch material. If scissors are used to open the pouch, this should be done close to the sealed edge so as not to damage the patch inside. The release liner for the patch is slit. Fold the patch in the middle and remove each half of the liner separately. Avoid touching the adhesive side of the patch. Apply the patch to the skin by applying light pressure with the palm of the hand for about 30 seconds. Make certain that the edges of the patch are adhering properly. Then wash hands with clean water.

Victanyl may be worn continuously for 72 hours. A new patch should 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 the skin.

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 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 or to any of the excipients listed in section 6.1.

Acute pain because there is no opportunity for dose titration during short-term use, or postoperative pain because persistent post-operative opioid use or serious or life-threatening hypoventilation could result.

Severe respiratory depression.

Contraindicated in opioid naïve patients.

4.4 Special warnings and precautions for use

PATIENTS WHO HAVE EXPERIENCED SERIOUS ADVERSE EVENTS SHOULD BE MONITORED FOR AT LEAST 24 HOURS AFTER REMOVAL OF VICTANYL, OR MORE, AS CLINICAL SYMPTOMS DICTATE, BECAUSE SERUM FENTANYL CONCENTRATIONS DECLINE GRADUALLY AND ARE REDUCED BY ABOUT 50% 20 TO 27 HOURS LATER.

Patients and their carers must be instructed that Victanyl contains an active substance in an amount that can be fatal, especially to a child. Therefore, they must keep all patches out of the sight and reach of children, both before and after use.

Because of the risks, including fatal outcome, associated with accidental ingestion, misuse, and abuse, patients and their carers must be advised to keep Victanyl patches in a safe and secure place, not accessible by others.

Opioid-naïve and not opioid-tolerant states

Use of transdermal fentanyl in the opioid-naïve patient has been associated with very rare cases of significant respiratory depression and/or fatality when used as initial opioid therapy, especially in patients with non-cancer pain. The potential for serious or life-threatening hypoventilation exists even if the lowest dose of transdermal fentanyl is used in initiating therapy in opioid-naïve patients, especially in elderly or patients with hepatic or renal impairment. The tendency of tolerance development varies widely among individuals. It is recommended that Victanyl is used in patients who have demonstrated opioid tolerance (see section 4.2).

Respiratory depression

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 transdermal fentanyl dose is increased (see section 4.9).

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA consider decreasing the total opioid dosage.

Risk from concomitant use of central nervous system (CNS) depressants, including sedative medicines such as benzodiazepines or related drugs, alcohol and CNS depressant narcotic drugs

Concomitant use of Victanyl and sedative medicines such as benzodiazepines or related drugs, alcohol or CNS depressant narcotic drugs, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Victanyl concomitantly with sedative medicines, the lowest effective dose should be used, and duration of treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Chronic pulmonary disease

Victanyl 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.

Long-term treatment effects and tolerance

In all patients, tolerance to the analgesic effects, hyperalgesia, physical dependence, and psychological dependence may develop upon repeated administration of opioids, whereas incomplete tolerance is developed for some side effects like opioid induced constipation. Particularly in patients with chronic non cancer pain, it has been reported that they may not experience a meaningful amelioration in pain intensity from continuous opioid treatment in the long term.

During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment (see section 4.2). When it is decided that there is no benefit for continuation, gradual down titration should be applied to address withdrawal symptoms.

Do not abruptly discontinue Victanyl in a patient physically dependent on opioids. Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Drug withdrawal syndrome

There have been reports that rapid tapering of Victanyl in a patient physically dependent on opioids may lead to serious withdrawal symptoms and uncontrolled pain (see section 4.2 and section 4.8). When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

Opioid use disorder (abuse and dependence)

Repeated use of Victanyl may lead to Opioid use disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Victanyl may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with Victanyl patches and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.

Patients treated with opioid medications should be monitored for signs of OUD, such as drug-seeking behaviour (e.g. too early requests for refills), particularly with patients at increased risk. This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered. If opioid discontinuation is to occur, see section 4.4.

Central Nervous System conditions including 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 should therefore be administered with caution to patients with bradyarrhythmias.

Hypotension

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).

Renal impairment

Even though impairment of renal function is not expected to affect fentanyl elimination to a clinically relevant extent, caution is advised because fentanyl pharmacokinetics has not been evaluated in this patient population (see section 5.2). Treatment should only be considered if the benefits outweigh the risks. If patients with renal impairment receive Victanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary. Additional restrictions apply to opioid-naïve patients with renal impairment (see section 4.2).

Fever/external heat application

Fentanyl concentrations may increase if the skin temperature increases (see section 5.2). Therefore, patients with fever should be monitored for opioid undesirable 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.

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

Serotonin syndrome

Caution is advised when Victanyl is co-administered with medicinal products that affect the serotonergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic active substances such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with active substances that impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose (see section 4.5).

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. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, treatment with Victanyl should be discontinued.

Interactions with other medicinal products

CYP3A4 inhibitors

The concomitant use of Victanyl with cytochrome P450 3A4 (CYP3A4) inhibitors 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. Therefore, the concomitant use of Victanyl and CYP3A4 inhibitors is not recommended unless the benefits outweigh the increased risk of adverse effects. Generally, a patient should wait for 2 days after stopping treatment with a CYP3A4 inhibitor before applying the first Victanyl patch. However, the duration of inhibition varies and for some CYP3A4 inhibitors with a long elimination half-life, such as amiodarone or for time-dependent inhibitors such as erythromycin, idelalisib, nicardipine and ritonavir, this period may need to be longer. Therefore, the product information of the CYP3A4 inhibitor must be consulted for the active substance’s half-life and duration of the inhibitory effect before applying the first Victanyl patch. A patient who is treated with Victanyl should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor. If concomitant use of Victanyl with a CYP3A4 inhibitor cannot be avoided, close monitoring for signs or symptoms of increased or prolonged therapeutic effects and adverse effects of fentanyl (in particular respiratory depression) is warranted, and the Victanyl dosage must be reduced or interrupted as deemed necessary (see section 4.5).

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).

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

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 Victanyl should be stopped.

Patients with myasthenia gravis

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

Concomitant use of mixed opioid agonists/antagonists

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see section 4.5).

MRI scan

The fentanyl transdermal patch contains metal. The patch should be removed before MRI scan since it can overheat during an MRI scan and cause skin burns in the immediate area of the patch.

Paediatric population

Victanyl should not be administered to opioid naïve paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of Victanyl transdermal system administered.

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

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

Opioid induced hyperalgesia

Opioid induced hyperalgesia (OIH) is a paradoxical response to an opioid in which there is an increase in pain perception despite stable or increased opioid exposure. It differs from tolerance, in which higher opioid doses are required to achieve the same analgesic effect or treat recurring pain. OIH may manifest as increased levels of pain, more generalised pain (i.e., less focal), or pain from ordinary (i.e. non-painful) stimuli (allodynia) with no evidence of disease progression. When OIH is suspected, the dose of opioid should be reduced or tapered off, if possible.

Endocrine effects

Opioids such as fentanyl may influence the hypothalamic-pituitary-adrenal or –gonadal axes, especially after long-term use. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may manifest from these hormonal changes. If an endocrine effect such as hyperprolactinaemia or adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Victanyl should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic-related interactions

Centrally-acting medicinal products/central nervous system (CNS) depressants, including alcohol and CNS depressant narcotic drugs

The concomitant use of Victanyl with other central nervous system depressants (including benzodiazepines and other sedatives/ hypnotics, opioids, general anaesthetics, phenothiazines, tranquilisers, sedating antihistamines, alcohol and CNS depressant narcotic drugs), skeletal muscle relaxants and gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death. Concomitant prescribing of CNS depressants and Victanyl should be reserved for patients for whom alternative treatment options are not possible. The use of any of these medicinal products concomitantly with Victanyl requires close monitoring and observation. The dose and duration of concomitant use should be limited (see section 4.4).

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

Serotonergic medicinal products

Co-administration of fentanyl with serotonergic medicinal products, 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. Use concomitantly with caution. Carefully observe the patient, particularly during treatment initiation and dose adjustment (see section 4.4).

Concomitant use of mixed opioid 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 section 4.4).

Pharmacokinetic-related interactions

Cytochrome P450 3A4 (CYP3A4) Inhibitors

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

The concomitant use of transdermal fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors 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. The extent of interaction with strong CYP3A4 inhibitors is expected to be greater than with weak or moderate CYP3A4 inhibitors. Cases of serious respiratory depression after coadministration of CYP3A4 inhibitors with transdermal fentanyl have been reported, including a fatal case after coadministration with a moderate CYP3A4 inhibitor. The concomitant use of CYP3A4 inhibitors and transdermal fentanyl is not recommended, unless the patient is closely monitored (see section 4.4). Examples of active substances that may increase fentanyl concentrations include: amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, nefazodone, ritonavir, verapamil, and voriconazole (this list is not exhaustive). After coadministration of weak, moderate or strong CYP3A4 inhibitors with short- term intravenous fentanyl administration, decreases in fentanyl clearance were generally ≤25%, however with ritonavir (a strong CYP3A4 inhibitor), fentanyl clearance decreased on average 67%. The extent of the interactions of CYP3A4 inhibitors with long-term transdermal fentanyl administration is not known, but may be greater than with short-term intravenous administration.

Cytochrome P450 3A4 (CYP3A4) Inducers

The concomitant use of transdermal fentanyl with CYP3A4 inducers may result in a decrease in fentanyl plasma concentrations and a decreased therapeutic effect. Caution is advised upon concomitant use of CYP3A4 inducers and Victanyl. The dose of Victanyl may need to be increased or a switch to another analgesic active substance may be needed. A fentanyl dose decrease and careful monitoring is warranted in anticipation of stopping concomitant treatment with a CYP3A4 inducer. The effects of the inducer decline gradually and may result in increased fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. Careful monitoring should be continued until stable drug effects are achieved. Examples of active substance that may decrease fentanyl plasma concentrations include: carbamazepine, phenobarbital, phenytoin and rifampicin (this list is not exhaustive).

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding

Administration to nursing women is not recommended as fentanyl may be secreted in breast milk and may cause respiratory depression in the infant.

Breastfeeding should therefore be discontinued during treatment with Victanyl and for at least 72 hours after removal of the patch.

Fertility

There are no clinical data on the effects of fentanyl on fertility. Some studies in rats have revealed reduced fertility and enhanced embryo mortality at maternally toxic doses (see section 5.3).

4.7 Effects on ability to drive and use machines

Victanyl 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 tranquilizers. Patients stabilized 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:

  • 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 transdermal fentanyl was evaluated in 1,565 adult and 289 paediatric subjects who participated in 11 clinical studies (1 double-blind, placebo-controlled; 7 open-label, active controlled; 3 open-label uncontrolled) used for the management of chronic malignant or non-malignant pain. These subjects received at least one dose of transdermal fentanyl and provided safety data. Based on pooled safety data from these clinical studies, the most commonly reported (i.e. ≥10% incidence) adverse reactions were: nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).

The adverse reactions reported with the use of transdermal fentanyl from these clinical studies, including the above-mentioned adverse reactions, and from post-marketing experiences are listed below in table 5.

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 clinical data).

The adverse reactions are presented by System Organ Class and in order of decreasing seriousness within each frequency category.

*The assigned frequency (uncommon) is based on analyses of incidence including only adult and paediatric clinical study subjects with non-cancer pain.

Paediatric population

The safety of transdermal fentanyl was evaluated in 289 paediatric subjects (<18 years) who participated in 3 clinical studies for the management of chronic or continuous pain of malignant or non-malignant origin. These subjects received at least one dose of transdermal fentanyl and provided safety data (see section 5.1).

The safety profile in children and adolescents treated with transdermal 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 transdermal fentanyl use in children as young as 2 years old when used as directed.

Based on pooled safety data from these 3 clinical studies in paediatric subjects, the most commonly reported (i.e. ≥10% incidence) adverse reactions were vomiting (33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%).

Tolerance

Tolerance can develop on repeated use.

Drug dependence

Repeated use of Victanyl patches can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

Opioid withdrawal symptoms

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 sections 4.2 and 4.4).

Neonatal withdrawal syndrome

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

Serotonin syndrome

Cases of serotonin syndrome have been reported when fentanyl was administered concomitantly with highly serotonergic drugs (see sections 4.4. and 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Symptoms and signs

The manifestations of fentanyl overdose are an extension of its pharmacologic actions, the most serious effect being respiratory depression. Toxic leukoencephalopathy has also been observed with fentanyl overdose.

Treatment

For management of respiratory depression, immediate countermeasures , include removing the Victanyl 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. 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

Fentanyl is an opioid analgesic with affinity mainly to the μ-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 0.3–1.5ng/ml; an increased incidence of adverse effects is observed if serum levels exceed 2ng/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.

Paediatric population

The safety of fentanyl transdermal patch 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, 30mg to 45mg oral morphine per day was replaced by one Fentanyl 12 micrograms/h transdermal patch. Starting dose of 25 micrograms/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45mg per dose of oral morphine.

5.2 Pharmacokinetic properties

Following administration of Fentanyl 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 Fentanyl transdermal patch, 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 Fentanyl transdermal patch size. For all practical purposes by the second 72-hour application, a steady state serum concentration is reached and is maintained during subsequent applications of a patch of the same size.

Distribution

The plasma protein binding for fentanyl is 84 %.

Biotransformation

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

Elimination

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

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

Pharmacokinetics in special groups

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 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).

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. Teratogenic 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 layer

Backing film

Polypropylene foil

Blue printing ink

Release liner

Polyethylene terephthalate foil (siliconised)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Each transdermal patch is packed in a separate sachet. The Composite foil containing the following layers from outside to inside: coated Kraft paper, low density polyethylene foil, aluminium foil, Surlyn

Pack containing 3 transdermal patches

Pack containing 4 transdermal patches

Pack containing 5 transdermal patches

Pack containing 8 transdermal patches

Pack containing 10 transdermal patches

Pack containing 16 transdermal patches

Pack containing 20 transdermal patches

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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.

7 MARKETING AUTHORISATION HOLDER

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

8 MARKETING AUTHORISATION NUMBER(S)

PL 00142/1161

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

27/05/2011

10 DATE OF REVISION OF THE TEXT

21/10/2025