Adults

This product is indicated for management of severe chronic pain that requires continuous long term opioid administration.

Children

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

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with fentanyl in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Posology

Opiodur/Fentanyl Zentiva 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 12, 25, 50, 75 and 100 mcg/h fentanyl to the systemic circulation, which represent about 0.3, 0.6, 1.2, 1.8, and 2.4 mg per day respectively.

Initial dose selection

The appropriate initiating dose of fentanyl should be based on the patient's current opioid use. It is recommended that Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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/hr to achieve the lowest appropriate dose of Opiodur/Fentanyl Zentiva depending on response and supplementary analgesic requirements.

Opioid-naive patients

Generally, the transdermal route is not recommended in opioid-naï ve patients. Alternative routes of administration (oral, parenteral) should be considered. To prevent overdose it is recommended that opioid-naï ve 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 Opiodur/Fentanyl Zentiva with a release rate of 12.5 mcg/h or 25 mcg/h is attained. Patients can then switch to Opiodur/Fentanyl Zentiva.

In the circumstance in which commencing with oral opioids is not considered possible and Opiodur/Fentanyl Zentiva is considered to be the only appropriate treatment option for opioid-naï ve 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 Opiodur/Fentanyl Zentiva is used in initiating therapy in opioid-naï ve patients (see sections 4.4 and 4.9).

Equianalgesic potency conversion

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

1. Calculate the 24-hour dose (mg/day) of the opioid currently being used.

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. To derive the Opiodur/Fentanyl Zentiva 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 for adult patients who are on 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 Opiodur/Fentanyl Zentiva based on daily oral morphine dose (for patients who have a need for opioid rotation or for clinically less stable patients: conversion ratio for oral morphine to transdermal fentanyl is approximately equal to 150:1)¹

1 In clinical studies these ranges of daily oral morphine doses were used as a basis for conversion to transdermal Opiodur/Fentanyl Zentiva

Table 3: Recommended starting dosage of Opiodur/Fentanyl Zentiva based on 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)

Initial evaluation of the maximum analgesic effect of Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva is attained.

Dose titration and maintenance therapy:

The Opiodur/Fentanyl Zentiva patch should be replaced every 72 hours.

The dose should be titrated individually on the basis of average daily use of supplement analgesics until a balance between analgesic efficacy and tolerability is attained. Dose titration should normally be performed in 12mcg/h or 25mcg/h increments, although the supplementary analgesic requirements (oral morphine 45/90 mg/day ≈ transdermal fentanyl12/25 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 Opiodur/Fentanyl Zentiva patch may be used for doses greater than 100mcg/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 Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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.

Treatment duration and goals

Before initiating treatment with Opiodur/Fentanyl Zentiva, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. 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).

Discontinuation of Opiodur/Fentanyl Zentiva

If discontinuation of Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva is removed; It may take 20 hours or more for the fentanyl serum concentration to decrease by 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 Opiodur/Fentanyl Zentiva and not from Opiodur/Fentanyl Zentiva 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-naï ve elderly patients, treatment should only be considered if the benefits outweigh the risks. In these cases, only Opiodur/Fentanyl Zentiva 12 mcg/h dosage should be considered for initial treatment.

Hepatic and renal impairment

Patients with impaired hepatic or renal function should be observed carefully and the dose should be individualized based upon the status of the patient (see sections 4.4 and 5.2).In opioid-naï ve patients with renal or hepatic impairment, treatment should only be considered if the benefits outweigh the risks. In these cases, only Opiodur/Fentanyl Zentiva 12 mcg/ h dosage should be considered for initial treatment.

Paediatric population

Children aged 16 years and above

Follow adult dosage.

Generally Opiodur/Fentanyl Zentiva should be administered only to opioid-tolerant paediatric patients (ages 2 to 16) who are already receiving at least 30 mg oral morphine equivalents per day. To convert paediatric patients from oral or parenteral opioids to Opiodur/Fentanyl Zentiva, refer to Equianalgesic potency conversion (Table 1), and Recommended Opiodur/Fentanyl Zentiva dose based upon daily oral morphine dose (Table 4).

Table 4: Recommended Opiodur/Fentanyl Zentiva dosage for paediatric patients¹based upon daily oral morphine dose²

1 Conversion to Opiodur/Fentanyl Zentiva dosages greater than 25 mcg/hr is the same for adult and paediatric patients

(see Table 2)

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

The analgesic effect of the first dose of Opiodur/Fentanyl Zentiva patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Opiodur/Fentanyl Zentiva, 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 fentanyl therapy or up-titration of the dose (see section 4.4)

Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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

Opiodur/Fentanyl Zentiva is for transdermal use.

Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva application requires cleansing prior to application of the patch, this should be done with clear water. Soaps, oils, lotions, or any other agents 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.

Opiodur/Fentanyl Zentiva should be applied immediately upon removal from the sealed package. To remove the patch from the protective sachet, locate the pre-cut notch or the cutting mark (indicated by an arrow on the patch label) along the edge of the seal. Gently tear or cut off the edge of the sachet completely. Further open along both sides, folding the sachet open like a book. Remove the shiny plastic backing, which covers the printed side of the patch. Carefully peel off one corner of the patch from the shiny plastic backing which covers the sticky side of the patch. 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.

Opiodur/Fentanyl Zentiva 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.

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

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

Severe respiratory depression.

Contraindicated in opioid naive patients.

Patients who have experienced serious adverse events should be monitored for at least 24 hours after removal of Opiodur/Fentanyl Zentiva, 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 Opiodur/Fentanyl Zentiva contains an active substance in an amount that can be fatal, especially to a child. Therefore, they must keep all patched 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 Opiodur/Fentanyl Zentiva in a safe and secure place, not accessible by others.

Opioid-naive and not opioid-tolerant states

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

Respiratory depression

Some patients may experience significant respiratory depression with Opiodur/Fentanyl Zentiva and patients must be observed for these effects. Respiratory depression may persist beyond the removal of the Opiodur/Fentanyl Zentiva patch. The incidence of respiratory depression increases as the Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva concomitantly with sedative medicines, the lowest effective dose should be used, and the 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

Opiodur/Fentanyl Zentiva 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.

Opioid use disorder (abuse and dependence)

Repeated use of Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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).

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with fentanyl.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. 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.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment (see section 4.2).

Central nervous system conditions including increased intracranial pressure

Opiodur/Fentanyl Zentiva 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.

Opiodur/Fentanyl Zentiva 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 bradyarrhythmia.

Hypotension

Opioids may cause hypotension, especially in patients with hypovolemia. 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 Opiodur/Fentanyl Zentiva they should be observed carefully for signs of fentanyl toxicity and the dose of Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary ). Additional restrictions apply to opioid-naï ve 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 Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva application site to direct external heat sources such as heating pads, hot water bottles, electric blankets, heated water beds, heat or tanning lamps, sun bathing, prolonged hot baths, saunas or hot whirlpool spa baths.

Serotonin Syndrome

Caution is advised when Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva should be discontinued.

Interactions with other Medicinal Products:

CYP3A4 Inhibitors:

The concomitant use of Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva 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 Opiodur/Fentanyl Zentiva patch. However, the duration of inhibition varies and for some CYP34 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 CYP34 inhibitor must be consulted for the active substance's half-life and duration of the inhibitory effect before applying the first Opiodur/Fentanyl Zentiva patch. A patient who is treated with Opiodur/Fentanyl Zentiva should wait at least 1 week after removal of the last patch before initiating treatment with a CYP34 inhibitor. If a concomitant use of Opiodur/Fentanyl Zentiva with CYP3A4 inhibitor cannot be avoided, close monitoring for signs or symptoms of increased or prolonged therapeutic effects and adverse effects or fentanyl (in particular respiratory depression) is warranted, and the Opiodur/Fentanyl Zentiva 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 the elderly patients may have reduced clearance and a prolonged half-life and may be more sensitive to the active substance than younger patients.. If elderly patients receive Opiodur/Fentanyl Zentiva 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 to take 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 Opiodur/Fentanyl Zentiva 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 also section 4.5).

Paediatric population

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

Opiodur/Fentanyl Zentiva has not been studied in children under 2 years of age. Fentanyl 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 Opiodur/Fentanyl Zentiva (see sections 4.2 and 6.6) and monitor adhesion of the patch closely.

Pharmacodynamic-related interactions

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

The concomitant use of Opiodur/Fentanyl Zentiva 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, hypoventilation, hypotension, profound sedation, coma or death. Concomitant prescribing of CNS depressants and Opiodur/Fentanyl Zentiva should be reserved for patients for whom alternative treatment options are not possible. The use of any of these medicinal products concomitantly with Opiodur/Fentanyl Zentiva requires close monitoring and observation. The dose and duration of concomitant use should be limited (see section 4.4)

Monoamine Oxidase Inhibitors (MAOI)

Opiodur/Fentanyl Zentiva is not recommended for use in patients who require the concomitant administration of a MAOI. Severe and unpredictable interactions with MAOIs, involving the potentiation of opiate effects or the potentiation of serotoninergic effects, have been reported. Therefore, Opiodur/Fentanyl Zentiva should not be used within 14 days after discontinuation of treatment with MAOIs.

Serotonergic medicinal products

Coadministration of fentanyl with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition. 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 dependant 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 Opiodur/Fentanyl Zentiva with cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic effects and the adverse effects, and which 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 Opiodur/Fentanyl Zentiva 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 decrease in fentanyl plasma concentrations and a decreased therapeutic effect. Caution is advised upon concomitant use of CYP3A4 inducers and Opiodur/Fentanyl Zentiva. The dose of Opiodur/Fentanyl Zentiva may need to be increased or 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 CP3A4 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.

Pregnancy

There are no adequate data from the use of Opiodur/Fentanyl Zentiva 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 anesthetic has been found to cross the placenta in human pregnancies. Opiodur/Fentanyl Zentiva should not be used in 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 Opiodur/Fentanyl Zentiva and for at least 72 hours after the 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).

Opiodur/Fentanyl Zentiva may impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving or operating machinery.

The safety of transdermal fentanyl patches was evaluated in 1565 adult and 289 paediatric subjects who participated in 11 clinical trials (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 patches and provided safety data. Based on pooled safety data from these clinical studies, the most commonly reported adverse drug reactions (ADRs) (i.e ≥ 10% incidence) 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 patches from these clinical trials, including the above-mentioned ADRs, 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); and Not known (cannot be estimated from the available clinical trial 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.

Tolerance

Tolerance can develop on repeated use.

Drug dependence

Repeated use of Opiodur/Fentanyl Zentiva 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).

Paediatric population

The safety of transdermal fentanyl patches 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 patches and provided safety data (see section 5.1).

The safety profile in children and adolescents treated with transdermal fentanyl patches was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with transdermal fentanyl patches 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%), diarrhea (12.8%), and pruritus (12.8%).

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to Opiodur/Fentanyl Zentiva or if therapy is stopped suddenly (see sections 4.2 and 4.4).

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

Cases of serotonin syndrome have been reported when fentanyl was administered concomitantly with serotonergic drugs (see section 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 professional 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.

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 pharmacological 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 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.

Pharmacotherapeutic group: opioids; phenylpiperidine derivatives, ATC Code: N02AB03

Mechanism of action

Fentanyl is an opioid analgesic which interacts predominantly with the µ -receptor. Its principal therapeutic effects are analgesia and sedation.

Paediatric population

The safety of transdermal fentanyl patches was evaluated in three open-label trials in 289 paediatric patients with chronic pain, 2 years of age to 17 years of age inclusive. Eighty of the children were aged to 2 to 6 years, inclusive. Of the 289 subjects enrolled in these 3 studies 110 initiated transdermal fentanyl patches treatment with a dosage of 12 mcg/h. Of these 110 subjects, 23 (20.9%) had previously been receiving 30 mg of oral morphine equivalents per day, 66 (60.0%) had been receiving 30 to 44 mg of oral morphine equivalents per day, and 12 (10.9%) had been receiving at least 45 mg of oral morphine equivalents per day (data not available for 9 [8.2%] subjects). Starting dosages of 25 mcg/h and higher were used by the remaining 179 patients, 174 (97.2%) of whom had been on prior daily opioid doses of at least 45 mg per dose of oral morphine equivalents per day. Among the remaining 5 subjects with a starting dosage of at least 25mcg/h whose prior opioid doses were <45 mg of oral morphine equivalents per day 1 (0.6%) had previously been receiving < 30 mg of oral morphine equivalents per day and 4 (2.2%) had been receiving 30 to 44 of oral morphine equivalents per day (see section 4.8).

Absorption

Opiodur/Fentanyl Zentiva provides continuous systemic delivery of fentanyl during the 72 hour application period. Following Opiodur/Fentanyl Zentiva application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. . The polymer matrix and the diffusion of fentanyl through the layers of the skin ensure that the release rate is relatively constant. The concentration gradient existing between the system and the lower concentration in the skin drives drug release. The average bioavailability of fentanyl after application of the transdermal patch is 92%,

After the first Opiodur/Fentanyl Zentiva 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. By the end of 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. Due to accumulation, the AUC and C_max values over a dosing interval at steady state are approximately 40% higher than after a single application. Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl. Higher inter-subject variability in plasma concentrations has been observed.

A pharmacokinetic model has been 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.

Skin temperature elevation may enhance the absorption of transdermally -applied fentanyl (see section 4.4). An increase in skin temperature through the application of a heating pad on low setting over the transdermal Opiodur/Fentanyl Zentiva system during the first 10 hours of a single application increased the mean fentanyl AUC value by 2.2-fold and the mean concentration at the end of heat application by 61%.

Distribution

Fentanyl is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (3 to 10 L/kg after intravenous dosing in patients). Fentanyl accumulates in skeletal muscle and fat and is released slowly into blood.

In a study in cancer patients treated with transdermal fentanyl, plasma protein binding was on average 95% (range 77-100%). Fentanyl crosses the blood-brain barrier easily. It also crosses the placenta and is excreted in breast milk.

Biotransformation

Fentanyl is a high clearance active substance and is rapidly and extensively metabolised primarily by CYP3A4 in the liver . The major metabolite, nor fentanyl, and other metabolites are 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 system circulation.

Elimination

Following a 72-hour patch application, the mean fentanyl half-lifer ranges from 20 to 27 hours. As a result of continued absorption of fentanyl from the skin depot after removal of the patch, the half-life of fentanyl after transdermal administration is about 2- to 3-fold longer than intravenous administration.

After intravenous administration, fentanyl mean total clearance values across studies range in general between 34 and 66 L/h.

Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted into the urine and approximately 9% of the dose into the faeces. Excretion occurs primarily, as metabolites, with less than 10% of the dose excreted as unchanged active substance.

Linearity/non-linearity

The serum fentanyl concentrations attained are proportional to the transdermal Opiodur/Fentanyl Zentiva patch size, The pharmacokinetics of transdermal fentanyl do not change with repeated application.

Pharmacokinetics/Pharmacodynamic Relationships

There is a high inter-subject variability in fentanyl pharmacokinetics, in the relationships between fentanyl concentrations, therapeutic and adverse effects, and in opioid tolerance. The minimum effective fentanyl concentration depends on the pain intensity and the previous use of opioid therapy. Both the minimum effective concentration and the toxic concentration increase with tolerance. An optimal therapeutic concentration range of fentanyl can therefore not be established.

Adjustment of the individual fentanyl dose must be based on the patient's response and level of tolerance. A lag time of 12 to 24 hours after application of the first patch and after a dose increase must be taken into account.

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 transdermal fentanyl patches, healthy elderly subject 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 4.4)

Renal impairment

The influence of renal impairment of the pharmacokinetics of fentanyl is expected to be limited because urinary excretion of unchanged fentanyl is less than 10% and there are no known active metabolites eliminated by the kidney. However, as the influence of renal impairment on the pharmacokinetics of fentanyl has not been evaluated, caution is advised (see sections 4.2 and 4.4).

Hepatic impairment

Patients with hepatic impairment should be carefully observed for signs of fentanyl toxicity and the dose of Opiodur/Fentanyl Zentiva should be reduced if necessary (see section 4.4). Data in subjects with cirrhosis and simulated data in subjects with different grades of impaired liver function treated with transdermal fentanyl suggest that fentanyl concentrations may be increased, and fentanyl clearance may be decreased compared to subjects with normal liver function. The simulations suggest that the steady-state AUC of patients with Child-Pugh Grade B liver disease (Child-Pugh Score = 8) would be approximately 1.36 times larger compared with that of patients with normal liver function (Grade A; Child-Pugh Score = 5.5). As for patients with Grade C liver disease (Child-Pugh Score = 12.5), the results indicate that fentanyl concentration accumulated with each administration, leading these patients to have an approximately 3.72 times larger AUC at steady state.

Paediatric population

Fentanyl concentrations were measured in more than 250 children aged 2 to 17 years who were applied fentanyl patches in the dose range of 12.5 to 300 mcg/h. Adjusting for body weight, clearance (L/h/kg) appears to be approximately 80% higher in children 2 to 5 years old and 25% higher in children 6 to 10 years old compared to children 11 to 16 years old, who are expected to have a similar clearance as adults. These findings have taken into consideration in determining the dosing recommendations for paediatric patients (see sections 4.2 and 4.4).

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Standard reproductive and developmental toxicity studies have been carried out using parenteral administration of fentanyl. In a rat study fentanyl did not influence male fertility. Some studies with female rats revealed reduced fertility and enhanced embryo mortality.

Effects on the embryo were due to maternal toxicity and not to direct effects of the substance on the developing embryo. These was no indication of teratogenic effects in studies in two species (rats and rabbits). In a study on pre- and postnatal development the survival rate of offspring was significantly reduced at doses that slightly reduced maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl on the pups. Effects on somatic development and behaviour of the offspring were not observed.

Mutagenicity testing in bacteria and in rodents yielded negative results. Fentanyl induced mutagenic effects in mammalian cells in vitro, comparable to other opioid analgesics. A mutagenic risk for the use of therapeutic doses seems unlikely since appeared only at high concentrations. A carcinogenicity study (daily subcutaneous injections of fentanyl hydrochloride for two years in Sprague Dawley rats) did not induce any findings indicative of oncogenic potential.

Overlay liner

Polyethylene terephthalate film with fluorocarbon release coating.

Backing Layer

Pigmented polyethylene terephthalate/ethylene vinyl acetate copolymer film

Drug adhesive Layer

Silicone adhesive (dimethicone, silicate resin)

Dimethicone

Rate controlling membrane

Ethylene vinyl acetate copolymer film

Skin adhesive Layer

Silicone adhesive (dimethicone, silicate resin)

Dimethicone

Release liner

Polyethylene terephthalate film with fluorocarbon release coating

Printing inks

Beige and orange

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

3 years

Do not store above 25° C.

Store in the original package in order to protect from moisture.

Each transdermal patch is packaged between two sheets of a multi-laminate pouching material, containing aluminium foil as the primary barrier component and a layer of ionomer resin attached to the aluminium layer, and in direct contact with the product. The two sheets of the multilaminate film are sealed together at the edges so as to enclose the product in a child resistant sachet.

Pack sizes:

Package containing 3 individually sealed transdermal patches

Package containing 4 individually sealed transdermal patches

Package containing 5 individually sealed transdermal patches

Package containing 8 individually sealed transdermal patches

Package containing 9 individually sealed transdermal patches

Package containing 10 individually sealed transdermal patches

Package containing 16 individually sealed transdermal patches

Package containing 19 individually sealed transdermal patches

Package containing 20 individually sealed transdermal patches

Not all pack sizes may be marketed.

High quantities of fentanyl remain in the transdermal patches even after use. Any unused medicinal product and any used transdermal patches should be folded so that the adhesive side of the patch adheres to itself and then they should be safely discarded. Unused patches should be returned to the (hospital) pharmacy according to the local requirements, as applicable.