4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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-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 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-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 Opiodur/Fentanyl Zentiva 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 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)

Prior Opioid

Route of Administration

Multiplication Factor

morphine

oral

1a*

parenteral

3

buprenorphine

sublingual

75

parenteral

100

codeine

oral

0.15

parenteral

0.23b

diamorphine

oral

0.5

parenteral

6b

fentanyl

oral

-

parenteral

300

hydromorphone

oral

4

parenteral

20b

ketobemidone

oral

1

parenteral

3

levorphanol

oral

7.5

parenteral

15b

methadone

oral

1.5

parenteral

3b

oxycodone

oral

1.5

parenteral

3

oxymorphone

rectal

3

parenteral

30b

pethidine

oral

-

parenteral

0.4b

tapentadol

oral

0.4

parenteral

-

tramadol

oral

0.25

parenteral

0.3

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

Oral 24-hour morphine (mg/ day)

Opiodur/Fentanyl Zentiva 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 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)

Oral 24-hour morphine (mg/day )

Opiodur/Fentanyl Zentiva 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 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 supplemental 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-naïve 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-naïve 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.

Children 2 to 16 years old

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

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

Oral 24-hour morphine (mg/day)

Opiodur/Fentanyl Zentiva Dosage (mcg/h)

30-44

45-134

12

25

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 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 fentanyl transdermal patch of 12 mcg/h. 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.

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 post-operative pain because persistent post-operative opioid use or serious or life threatening hypoventilation could result.

Severe respiratory depression.

Contraindicated in opioid naive 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 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 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 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.

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 Opiodur/Fentanyl Zentiva in a patient physically dependent on opioids. Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction.

There have been reports that rapid tapering of Opiodur/Fentanyl Zentiva 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 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-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 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 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 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 CYP3A4 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.

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 Opiodur/Fentanyl Zentiva 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 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 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 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 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 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 anaesthetic 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).

4.7. Effects on ability to drive and use machines

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

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

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

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

o It was not affecting your ability to drive safely.

4.8. Undesirable effects

The safety of transdermal fentanyl patches was evaluated in 1565 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 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 studies, 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.

Table 5: Adverse reactions in adult and paediatric patients

System Organ Class

Frequency Category

Very Common

Common

Uncommon

Rare

Not Known

Immune System Disorders

Hypersensitivity

Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction

Endocrine disorders

Androgen deficiency

Metabolism and Nutrition Disorders

Anorexia

Psychiatric Disorders

.

Insomnia, Depression, Anxiety, Confusional state, Hallucination

Agitation, Disorientation, Euphoric mood

Delirium, Drug dependence (see section 4.4)

Nervous System Disorders

Somnolence Dizziness, Headache

Tremor, Paraesthesia

Hypoaesthesia, Convulsion (including clonic convulsions and grand mal convulsion), Amnesia, Depressed level of consciousness , Loss of consciousness

Eye Disorders

Vision blurred

Miosis

Ear and Labyrinth Disorders

Vertigo

Cardiac Disorders

Palpitations, Tachycardia

Bradycardia, Cyanosis

Vascular Disorders

Hypertension

Hypotension

Respiratory, Thoracic and Mediastinal Disorders

Dyspnoea

Respiratory depression, Respiratory distress

Apnoea, Hypoventilation

Bradypnoea,

Gastrointestinal Disorders

Nausea, Vomiting, Constipation

Diarrhoea, Dry mouth, Abdominal pain, Abdominal pain upper, Dyspepsia

Ileus, Dysphagia

Subileus

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis, Pruritus, Rash, Erythema

Eczema, Dermatitis allergic, Skin disorder, Dermatitis, Dermatitis contact

Musculoskeletal and Connective Tissue Disorders

Muscle spasms

Muscle twitching

Renal and Urinary Disorders

Urinary retention

Reproductive System and Breast Disorders

Erectile dysfunction, Sexual dysfunction

General Disorders and Administration Site Conditions

Fatigue, Oedema peripheral, Asthenia, Malaise, Feeling cold

Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivity, Drug withdrawal syndrome, Pyrexia*.

Application site dermatitis, Application site eczema

Drug tolerance

*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 syndrome

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).

Neonatal withdrawal syndrome

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).

Serotonin syndrome

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.

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 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.