Fentanyl HEXAL

Management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain. Breakthrough pain is a transient exacerbation of otherwise controlled chronic background pain.

Fentanyl HEXAL citrate is an opioid analgesic used:

In low doses to provide analgesia during short surgical procedures.

In high doses as an analgesic/respiratory depressant in patients requiring assisted ventilation.

In combination with a neuroleptic in the technique of neuroleptanalgesia.

In the treatment of severe pain, such as the pain of myocardial infarction.

Adults

Fentanyl HEXAL DTrans 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 from 2 years of age who are receiving opioid therapy.

Fentanyl HEXAL is indicated for the management of acute moderate to severe post-operative pain in adult patients.

Fentanyl HEXAL is indicated for the management of breakthrough pain in patients already receiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.

Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Fentanyl HEXAL is indicated for the treatment of breakthrough pain (BTP) in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain.

BTP is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.

Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Fentanyl HEXAL is indicated for the management of breakthrough pain (BTP) in adults who are already receiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.

Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Fentanyl HEXAL should only be administered to patients who are considered tolerant to their opioid therapy for persistent cancer pain. Patients can be considered opioid tolerant if they take at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Method of administration:

Fentanyl HEXAL sublingual tablets should be administered directly under the tongue at the deepest part. Fentanyl HEXAL sublingual tablets should not be swallowed, but allowed to completely dissolve in the sublingual cavity without chewing or sucking. Patients should be advised not to eat or drink anything until the sublingual tablet is completely dissolved.

In patients who have a dry mouth water may be used to moisten the buccal mucosa before taking Fentanyl HEXAL.

Dose titration:

The object of dose titration is to identify an optimal maintenance dose for ongoing treatment of breakthrough pain episodes. This optimal dose should provide adequate analgesia with an acceptable level of adverse reactions.

The optimal dose of Fentanyl HEXAL will be determined by upward titration, on an individual patient basis. Several doses are available for use during the dose titration phase. The initial dose of Fentanyl HEXAL used should be 100 micrograms, titrating upwards as necessary through the range of available dosage strengths.

Patients should be carefully monitored until an optimal dose is reached.

Switching from other fentanyl containing products to Fentanyl HEXAL must not occur at a 1:1 ratio because of different absorption profiles. If patients are switched from another fentanyl containing product, a new dose titration with Fentanyl HEXAL is required.

The following dose regimen is recommended for titration, although in all cases the physician should take into account the clinical need of the patient, age and concomitant illness.

All patients must start therapy with a single 100 microgram sublingual tablet. If adequate analgesia is not obtained within 15-30 minutes of administration of a single sublingual tablet, a supplemental (second) 100 microgram sublingual tablet may be administered. If adequate analgesia is not obtained within 15-30 minutes of the first dose an increase in dose to the next highest tablet strength should be considered for the next episode of breakthrough pain (Refer to figure below).

Dose escalation should continue in a stepwise manner until adequate analgesia with tolerable adverse reactions is achieved. The dose strength for the supplemental (second) sublingual tablet should be increased from 100 to 200 micrograms at doses of 400 micrograms and higher. This is illustrated in the schedule below. No more than two (2) doses should be administered for a single episode of breakthrough pain during this titration phase.

If adequate analgesia is achieved at the higher dose, but undesirable effects are considered unacceptable, an intermediate dose (using the 100 microgram sublingual tablet where appropriate) may be administered.

During titration, patients can be instructed to use multiples of 100 microgram tablets and/or 200 microgram tablets for any single dose. No more than four (4) tablets should be used at any one time.

The efficacy and safety of doses higher than 800 micrograms have not been evaluated in clinical studies in patients.

In order to minimise the risk of opioid-related adverse reactions and to identify the appropriate dose, it is imperative that patients be monitored closely by health professionals during the titration process.

During titration patients should wait at least 2 hours before treating another episode of breakthrough pain with Fentanyl HEXAL.

Maintenance therapy:

Once an appropriate dose has been established, which may be more than one tablet, patients should be maintained on this dose and should limit consumption to a maximum of four Fentanyl HEXAL doses per day.

During the maintenance period patients should wait at least 2 hours before treating another episode of breakthrough pain with Fentanyl HEXAL.

Dose re-adjustment:

If the response (analgesia or adverse reactions) to the titrated Fentanyl HEXAL dose markedly changes, an adjustment of dose may be necessary to ensure that an optimal dose is maintained.

If more than four episodes of breakthrough pain are experienced per day over a period of more than four consecutive days, then the dose of the long acting opioid used for persistent pain should be re-evaluated. If the long acting opioid or dose of long acting opioid is changed the Fentanyl HEXAL dose should be re-evaluated and re-titrated as necessary to ensure the patient is on an optimal dose.

It is imperative that any dose re-titration of any analgesic is monitored by a health professional.

Discontinuation of therapy:

Fentanyl HEXAL should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for the persistent background pain should be kept as prescribed.

If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor in order to avoid the possibility of abrupt withdrawal effects.

Use in children and adolescents:

Fentanyl HEXAL must not be used in patients less than 18 years of age due to a lack of data on safety and efficacy.

Use in older people:

Dose titration needs to be approached with particular care and patients observed carefully for signs of fentanyl toxicity.

Use in patients with renal and hepatic impairment

Patients with kidney or liver dysfunction should be carefully observed for signs of fentanyl toxicity during the Fentanyl HEXAL titration phase.

Routes of administration

Fentanyl HEXAL should be given only in an environment where the airway can be controlled and by personnel who can control the airway

Intravenous administration, either as a bolus or by infusion.

Intramuscular administration.

To avoid bradycardia, it is recommended to administer a small intravenous dose of an anti-cholinergic just before anaesthetic induction.

Posology

Fentanyl HEXAL Injection 50 micrograms/ml, by the intravenous route, can be administered to both adults and children. The dose of Fentanyl HEXAL Injection 50 micrograms/ml should be individualised according to age, body weight, physical status, underlying pathological condition, use of other drugs and type of surgery and anaesthesia.

Adults

The usual dosage regime is as follows:

Doses in excess of 200 micrograms are for use in anaesthesia only.

As a premedicant, 1-2 ml Fentanyl HEXAL Injection 50 micrograms/ml may be administered intramuscularly 45 minutes before induction of anaesthesia.

After intravenous administration in unpremedicated adult patients, 2 ml of Fentanyl HEXAL Injection 50 micrograms/ml may be expected to provide sufficient analgesia for 10 - 20 minutes in surgical procedures involving low pain intensity. 10 ml Fentanyl HEXAL Injection 50 micrograms/ml injected as a bolus gives analgesia lasting about one hour. The analgesia produced is sufficient for surgery involving moderately painful procedures. Giving a dose of 50mcg/kg Fentanyl HEXAL Injection 50 micrograms/ml will provide intense analgesia for some four to six hours for intensely stimulating surgery.

Fentanyl HEXAL Injection 50 micrograms/ml may also be given as an infusion. In ventilated patients, a loading dose of Fentanyl HEXAL Injection 50 micrograms/ml may be given as a fast infusion of approximately 1 mcg/kg/min for the first 10 minutes followed by an infusion of approximately 0.1 mcg/kg/min. Alternatively the loading dose of Fentanyl HEXAL Injection 50 micrograms/ml may be given as a bolus. Infusion rates should be titrated to individual patient response; lower infusion rates may be adequate. Unless it is planned to ventilate post-operatively, the infusion should be terminated at about 40 minutes before the end of surgery.

Lower infusion rates, e.g. 0.05-0.08 mcg/kg/minute are necessary if spontaneous ventilation is to be maintained. Higher infusion rates (up to 3 mcg/kg/minute) have been used in cardiac surgery.

Fentanyl HEXAL Injection is chemically incompatible with the induction agents thiopentone and methohexitone because of wide differences in pH.

Use in elderly and debilitated patients: It is wise to reduce the dosage in the elderly and debilitated patients. The effect of initial dose should be taken into account in determining supplemental doses.

Paediatric population

Children aged 12 to 17 years old: Follow adult dosage.

Children aged 2 to 11 years old:

The usual dosage regimen in children is as follows:

Use in children:

Analgesia during operation, enhancement of anaesthesia with spontaneous respiration.

Techniques that involve analgesia in a spontaneous breathing child should only be used as part of an anaesthetic technique, or given as part of a sedation/analgesia technique with experienced personnel in an environment that can manage sudden chest wall rigidity requiring intubation, or apnoea requiring airway support.

It is important when estimating the required dose to assess the likely degree of surgical stimulation, the effect of premedicant drugs, and the duration of the procedure.

Obese patients:

In obese patients there is a risk of overdosing if the dose is calculated based on body weight. Obese patients should have dosage calculated according to their estimated ideal body mass.

Renal Impairment

Posology

Fentanyl HEXAL DTrans 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 dosage selection

The appropriate initiating dose of Fentanyl HEXAL DTrans should be based on the patient's current opioid use. It is recommended that Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans refer to Equianalgesic potency conversion below. The dosage may subsequently be titrated upwards or downwards, if required, in increments of either 12 or 25 mcg/h to achieve the lowest appropriate dosage of Fentanyl HEXAL DTrans depending on response and supplementary analgesic requirements.

Opioid-naïve patients

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

In the circumstance in which commencing with oral opioids is not considered possible and Fentanyl HEXAL DTrans is considered to be the only appropriate treatment option for opioid-naïve patients, only the lowest starting dose (ie, 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 Fentanyl HEXAL DTrans is used in initiating therapy in opioid-naïve patients.

Equianalgesic potency conversion

In patients currently taking opioid analgesics, the starting dose of Fentanyl HEXAL DTrans should be based on the daily dose of the prior opioid. To calculate the appropriate starting dose of Fentanyl HEXAL DTrans, 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 Fentanyl HEXAL DTrans dosage corresponding to the calculated 24-hour, equianalgesic morphine dosage, use dosage-conversion Table 2 or 3 as follows:

a. Table 2 is for adult patients who have a need for opioid rotation or who are less clinically stable (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 150:1).

b. Table 3 is for adult patients who are on a stable, and well-tolerated, opioid regimen (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 100:1).

Table 1: Conversion Table - Multiplication Factors for Converting the Daily Dose of Prior Opioids to the Equianalgesic 24-hour Oral Morphine Dose (mg/day Prior Opioid x Factor = Equianalgesic 24-hour Oral Morphine Dose)

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

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

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

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

¹ In clinical studies these ranges of daily oral morphine doses were used as a basis for conversion to Fentanyl HEXAL DTrans.

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

Initial evaluation of the maximum analgesic effect of Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans is attained.

Dose titration and maintenance therapy

The Fentanyl HEXAL DTrans patch should be replaced every 72 hours.

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

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

If analgesia is insufficient during the first application only, the Fentanyl HEXAL DTrans 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 (eg, 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 and the patient should be monitored closely.

Discontinuation of Fentanyl HEXAL DTrans

If discontinuation of Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans is removed. It may take 20 hours or more for the fentanyl serum concentrations to decrease 50%. In general, the discontinuation of opioid analgesia should be gradual in order to prevent withdrawal symptoms.

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 Fentanyl HEXAL DTrans and not from Fentanyl HEXAL DTrans 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.

In opioid-naïve elderly patients, treatment should only be considered if the benefits outweigh the risks. In these cases, only Fentanyl HEXAL DTrans 12 mcg/h dosage should be considered for initial treatment.

Renal and hepatic impairment

Patients with renal or hepatic impairment should be observed carefully and the dose should be individualised based upon the status of the patient.

In opioid-naïve patients with renal or hepatic impairment, treatment should only be considered if the benefits outweigh the risks. In these cases, only Fentanyl HEXAL DTrans 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

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

Table 4: Recommended Fentanyl HEXAL DTrans dosage for paediatric patients¹ based upon daily oral morphine dose²

¹ Conversion to Fentanyl HEXAL DTrans dosages greater than 25 mcg/h is the same for paediatric patients as it is for adult patients (see Table 2).

² In clinical studies these ranges of daily oral morphine doses were used as a basis for conversion to Fentanyl HEXAL DTrans.

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

The analgesic effect of the first dose of Fentanyl HEXAL DTrans patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Fentanyl HEXAL DTrans, 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 HEXAL DTrans therapy or up-titration of the dose .

Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans 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

Fentanyl HEXAL DTrans is for transdermal use.

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

Fentanyl HEXAL DTrans should be applied immediately upon removal from the sealed package. To remove the patch from the protective sachet, locate the pre-cut notch (indicated by an arrow on the patch label) along the edge of the seal. Fold the sachet at the notch, then carefully tear the sachet material. Further open the sachet along both sides, folding the sachet open like a book. The release liner for the patch is slit. Fold the patch in the middle and remove each half of the liner separately. Avoid touching the adhesive side of the patch. Apply the patch to the skin by applying light pressure with the palm of the hand for about 30 seconds. Make certain that the edges of the patch are adhering properly. Then wash hands with clean water.

Fentanyl HEXAL DTrans 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.

Fentanyl HEXAL is restricted to hospital use only. Treatment should be initiated by and remain under the guidance of a physician experienced in the management of opioid therapy. Due to the well-known potential of abuse of fentanyl, physicians should evaluate patients for a history of drug abuse.

Posology

Patients should be titrated to an acceptable level of analgesia prior to initiating use of Fentanyl HEXAL.

Fentanyl HEXAL should only be activated by the patient.

Each dose of Fentanyl HEXAL delivers 40 micrograms of fentanyl over a 10 minute period, to a maximum of 240 micrograms per hour (6 doses each of 10 minutes duration). Fentanyl HEXAL will operate for 24 hours after the system is assembled or for 80 doses, whichever comes first, and then becomes inoperative.

After 24 hours or 80 doses, a new system should be applied if necessary. Each new system should be placed on a new skin site. With each new Fentanyl HEXAL application the patient may use Fentanyl HEXAL more frequently than during the remainder of the 24 hour dosing period, due to a lower absorption of fentanyl from the system for the first few hours.

The maximum treatment duration is 72 hours, although the majority of patients should only need one system.

Patients should not wear more than one system at a time.

Used systems should not be reapplied to a patient.

Fentanyl HEXAL should be removed before the patient is discharged.

Elderly patients

As with all fentanyl products, the clearance of fentanyl may be reduced in elderly patients, with a consequent increase in half life. No specific dose adjustment is required in elderly patients. However elderly patients should be observed closely for adverse effects of fentanyl.

Hepatic or renal impairment

Fentanyl HEXAL should be administered with caution to patients with moderate or severe hepatic or renal impairment.

Paediatric population

The safety and efficacy of Fentanyl HEXAL in children and adolescents younger than 18 years of age has not been established.

Method of administration

Fentanyl HEXAL is for transdermal use only.

Precaution to be taken before manipulating or administering the product

Gloves should be worn when manipulating Fentanyl HEXAL. To avoid oral ingestion of the fentanyl-containing hydrogel, which may cause life-threatening hypoventilation or death, the hydrogel must not touch the mouth or other mucosal areas.

Patients should not get Fentanyl HEXAL wet. Prolonged contact with water could affect system performance and cause the system to fall off.

Preparation of application site

Fentanyl HEXAL should be applied to intact, non-irritated and non-irradiated skin. Fentanyl HEXAL should not be placed on abnormal skin sites, such as scars, burns, tattoos, etc. Fentanyl HEXAL should also not be placed on skin on which topical medicines have been applied. Hair at the application site should be clipped (not shaved) before system application. Fentanyl HEXAL should not be applied to a previously used skin site.

The application site should be wiped with a standard alcohol swab and the skin should be allowed to dry completely before Fentanyl HEXAL is applied. No soaps, oils, lotions, or any other agents that might irritate the skin or alter its absorption characteristics should be used to clean the application site.

Assembly of Fentanyl HEXAL

Fentanyl HEXAL should not be used if the seal on the tray or the sachet containing the Drug Unit is broken or damaged.

Gloves should be worn during the assembly of Fentanyl HEXAL. The tray is opened by pulling back on the tray lid. The sachet containing the Drug Unit should be opened starting at the pre-cut notch, then by carefully tearing along the top of the sachet. The Drug Unit should be removed from the sachet and the Controller should be snapped on by aligning the shape and firmly pressing the two parts together.

When assembled, the digital display of the Controller will complete a short self-test during which there will be an audible beep, the red light will flash once, and the digital display will flash the number 88. At the end of the self-test, the display will show the number 0 and a green light will flash at a slow rate to indicate Fentanyl HEXAL is ready for application.

Application of Fentanyl HEXAL

The clear plastic film covering the adhesive should be removed and discarded with care taken not to touch the hydrogels.

Dose delivery

A recessed dosing button is located on the Controller of Fentanyl HEXAL. To initiate administration of a fentanyl dose, the patient should press and release the dosing button twice within 3 seconds. Fentanyl HEXAL should only be activated by the patient.

Upon successful dose initiation, Fentanyl HEXAL will emit a beep indicating the start of delivery. The green light will change from a slow flash rate to a rapid flash rate and the digital display will alternate between a rotating circle and the number of completed doses during the entire 10-minute dose delivery period. The next dose cannot be initiated until the previous 10-minute delivery period is complete. Pressing the button during delivery of a dose will not result in additional fentanyl being administered. After the 10-minute dose has been completely delivered, the green light will return to a slow flash rate, the digital display will show the number of doses that have been delivered, and Fentanyl HEXAL will be ready to be used again by the patient.

At the end of 24 hours of use, or after 80 doses have been administered, the green light will switch off and the number of doses delivered will flash on and off. The flashing digital display may be turned off by pressing the dose button for six seconds.

Removal

Fentanyl HEXAL is removed from the patient by lifting the system at the red tab and peeling it away from the skin site. Gloves must be worn while removing Fentanyl HEXAL from the skin and care should be taken to avoid touching the hydrogels. If the medicinal product contacts the skin during removal, the contact area should be thoroughly rinsed with water without using any soap.

Fentanyl HEXAL may be removed at any time. However, once a system has been removed, the same system should not be reapplied. If the patient requires additional treatment for pain, a new system may be applied to a new skin site on the upper outer arm or chest.

Special precautions for disposal should be followed.

Troubleshooting

Each Fentanyl HEXAL system is designed to deliver up to 80 10-minute doses of fentanyl over a period of 24 hours. The table below represents the different error messages that may occur, together with the probable cause and the action to be taken.

If device failure or malfunction is suspected by a healthcare professional, Fentanyl HEXAL should be immediately removed from the patient and The Medicines Company contacted straightaway.

The healthcare professional must ensure the patient understands that if they suspect a device failure or malfunction, they must immediately inform a healthcare professional.

Posology

In order to minimise the risks of opioid-related adverse reactions and to identify the “successful” dose, it is imperative that patients be monitored closely by health professionals during the titration process.

Fentanyl HEXAL is not interchangeable on a mcg to mcg basis with other short-acting fentanyl products that are indicated for the use of breakthrough cancer pain, as the pharmacokinetic profiles and/or dosing schedules of these products are significantly different. Patients should be instructed not to use more than one short-acting fentanyl product concurrently for the treatment of breakthrough cancer pain, and to dispose of any fentanyl product prescribed for breakthrough pain (BTP) when switching to Fentanyl HEXAL. The number of Fentanyl HEXAL strengths available to the patient at any time should be minimised to prevent confusion and potential overdose.

Any unused Fentanyl HEXAL units that the patient no longer requires must be disposed of properly. Patients must be reminded of the requirements to keep Fentanyl HEXAL stored in a location away from children.

Adults

Dose titration and maintenance therapy

Fentanyl HEXAL should be individually titrated to a “successful” dose that provides adequate analgesia and minimises adverse reactions. In clinical trials the successful dose of Fentanyl HEXAL for breakthrough pain was not predicted from the daily maintenance dose of opioid.

a) Titration

Before patients are titrated with Fentanyl HEXAL, it is expected that their background persistent pain will be controlled by use of opioid therapy and that they are typically experiencing no more than 4 episodes of breakthrough pain per day.

The initial dose of Fentanyl HEXAL used should be 200 micrograms, titrating upwards as necessary through the range of available dosage strengths (200, 400, 600, 800, 1,200 and 1,600 micrograms). Patients should be carefully monitored until a dose is reached that provides adequate analgesia with acceptable adverse reactions using a single dosage unit per episode of breakthrough pain. This is defined as the successful dose.

During titration, if adequate analgesia is not obtained within 30 minutes after starting the first unit (i.e. 15 minutes after the patient completes consumption of a single Fentanyl HEXAL unit), a second Fentanyl HEXAL unit of the same strength may be consumed. No more than two Fentanyl HEXAL units should be used to treat any individual pain episode. At 1600 micrograms, a second dose is only likely to be required by a minority of patients.

If treatment of consecutive breakthrough pain episodes requires more than one dosage unit per episode, an increase in dose to the next higher available strength should be considered.

Fentanyl HEXAL Titration Process

*Available dosage strengths include: 200, 400, 600, 800, 1200, and 1600 micrograms

b) Maintenance

Once a successful dose has been established (i.e., on average, an episode is effectively treated with a single unit), patients should be maintained on this dose and should limit consumption to a maximum of four Fentanyl HEXAL units per day.

Patients should be monitored by a health professional to ensure that the maximum consumption of four units of Fentanyl HEXAL per day is not exceeded.

Dose re-adjustment

The maintenance dose of Fentanyl HEXAL should be increased when an episode is not effectively treated with a single unit for several consecutive BTP episodes. For dose-readjustment the same principles apply as outlined for dose titration (see above).

If more than four episodes of breakthrough pain are experienced per day the dose of the long acting opioid used for persistent pain should be re-evaluated. If the dose of the long acting opioid is increased, the dose of Fentanyl HEXAL to treat breakthrough pain may need to be reviewed.

It is imperative that any dose re-titration of any analgesic is monitored by a health professional.

Discontinuation of therapy

Fentanyl HEXAL should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for the persistent background pain should be kept as prescribed. If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor as gradual downward opioid titration is necessary in order to avoid the possibility of abrupt withdrawal effects.

Use in the elderly

Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously. Therefore dose titration needs to be approached with particular care. In the elderly, elimination of fentanyl is slower and the terminal elimination half-life is longer, which may result in accumulation of the active substance and to a greater risk of undesirable effects.

Formal clinical trials with Fentanyl HEXAL have not been conducted in the elderly. It has been observed, however, in clinical trials that patients over 65 years of age required lower doses of Fentanyl HEXAL for successful relief of breakthrough pain.

Use in patients with hepatic or renal impairment

Special care should be taken during the titration process in patients with kidney or liver dysfunction.

Paediatric population

Adolescents aged 16 years and above:

Follow adult dosage.

Children and adolescents below 16 years:

Safety and efficacy in children and adolescents below 16 years have not been established. There is limited clinical trial experience of the use of Fentanyl HEXAL in paediatric patients already receiving maintenance opioid therapy. Use in this patient population is therefore not recommended.

Method of administration

Fentanyl HEXAL is intended for oromucosal administration, and therefore should be placed in the mouth against the cheek and should be moved around the mouth using the applicator, with the aim of maximising the amount of mucosal exposure to the product. The Fentanyl HEXAL unit should be sucked, not chewed, as absorption of fentanyl via the buccal mucosa is rapid in comparison with systemic absorption via the gastrointestinal tract. Water may be used to moisten the buccal mucosa in patients with a dry mouth.

The Fentanyl HEXAL unit should be consumed over a 15 minute period. If signs of excessive opioid effects appear before the Fentanyl HEXAL unit is fully consumed it should be immediately removed, and consideration given to decreasing future dosages.

Treatment should be initiated by and remain under the guidance of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential of abuse of fentanyl. Patients should be instructed not to use two different formulations of fentanyl concurrently for the treatment of breakthrough pain, and to dispose of any fentanyl product prescribed for BTP when switching to Fentanyl HEXAL. The number of tablet strengths available to the patients at any time should be minimised to prevent confusion and potential overdose.

Posology

Dose titration

Fentanyl HEXAL should be individually titrated to an “effective” dose that provides adequate analgesia and minimises adverse reactions. In clinical studies, the effective dose of Fentanyl HEXAL for BTP was not predictable from the daily maintenance dose of opioid.

Patients should be carefully monitored until an effective dose is reached.

Titration in patients not switching from other fentanyl containing products

The initial dose of Fentanyl HEXAL should be 100 micrograms, titrating upwards as necessary through the range of available tablets strengths (100, 200, 400, 600, 800 micrograms).

Titration in patients switching from other fentanyl containing products

Due to different absorption profiles, switching must not be done at a 1:1 ratio. If switching from another oral fentanyl citrate product, independent dose titration with Fentanyl HEXAL is required as bioavailability between products differs significantly. However, in these patients, a starting dose higher than 100 micrograms may be considered.

Method of titration

During titration, if adequate analgesia is not obtained within 30 minutes after the start of administration of a single tablet, a second Fentanyl HEXAL tablet of the same strength may be used.

If treatment of a BTP episode requires more than one tablet, an increase in dose to the next higher available strength should be considered to treat the next BTP episode.

During titration, multiple tablets may be used: up to four 100 micrograms or up to four 200 micrograms tablets may be used to treat a single episode of BTP during dose titration according to the following schedule:

- If the initial 100 micrograms tablet is not efficacious, the patient can be instructed to treat the next episode of BTP with two 100 micrograms tablets. It is recommended that one tablet should be placed in each side of the mouth. If this dose is considered to be the effective dose, treatment of successive episodes of BTP may be continued with a single 200 micrograms tablet of Fentanyl HEXAL.

- If a single 200 micrograms tablet of Fentanyl HEXAL (or two 100 micrograms tablets) is not considered to be efficacious the patient can be instructed to use two 200 micrograms tablets (or four 100 micrograms tablets) to treat the next episode of BTP. It is recommended that two tablets should be placed in each side of the mouth. If this dose is considered to be the effective dose, treatment of successive episodes of BTP may be continued with a single 400 micrograms tablet of Fentanyl HEXAL.

- For titration to 600 micrograms and 800 micrograms, tablets of 200 micrograms should be used.

Doses above 800 micrograms were not evaluated in clinical studies.

No more than two tablets should be used to treat any individual BTP episode, except when titrating using up to four tablets as described above.

Patients should wait at least 4 hours before treating another BTP episode with Fentanyl HEXAL during titration.

Maintenance therapy

Once an effective dose has been established during titration, patients should continue to take this dose as a single tablet of that given strength. Breakthrough pain episodes may vary in intensity and the required Fentanyl HEXAL dose might increase over time due to progression of the underlying cancer disease. In these cases, a second tablet of the same strength may be used. If a second tablet of Fentanyl HEXAL was required for several consecutive times, the usual maintenance dose is to be readjusted (see below).

Patients should wait at least 4 hours before treating another BTP episode with Fentanyl HEXAL during maintenance therapy.

Dose readjustment

The maintenance dose of Fentanyl HEXAL should be increased when a patient requires more than one tablet per BTP episode for several consecutive BTP episodes. For dose-readjustment the same principles apply as outlined for dose titration (see above).

Dose readjustment of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours.

Discontinuation of therapy

Fentanyl HEXAL should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for the persistent background pain should be kept as prescribed.

If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor in order to manage the risk of abrupt withdrawal effects.

Hepatic or renal impairment

Fentanyl HEXAL should be administered with caution to patients with moderate or severe hepatic or renal impairment.

Patients with xerostomia

Patients experiencing xerostomia are advised to drink water to moisten the buccal cavity prior to administration of Fentanyl HEXAL. If this recommendation does not result in an appropriate effervescence, then a switch of therapy may be advised.

Use in the elderly (older than 65 years)

In clinical studies patients older than 65 years tended to titrate to a lower effective dose than younger patients. It is recommended that increased caution should be exercised in titrating the dose of Fentanyl HEXAL in elderly patients.

Paediatric population

The safety and efficacy of Fentanyl HEXAL in children aged 0 to 18 years have not been established. No data are available.

Method of administration

Fentanyl HEXAL tablet once exposed to moisture utilises an effervescent reaction to deliver the active substance. Therefore patients should be instructed not to open the blister until ready to place the tablet in the buccal cavity.

Opening the blister package

Patients should be instructed NOT to attempt to push the tablet through the blister because this could damage the buccal tablet. The correct method of releasing the tablet from the blister is:

One of the blister units should be separated from the blister card by tearing it apart at the perforations. The blister unit should then be flexed along the line printed on the backing foil where indicated. The backing foil should be peeled back to expose the tablet.

Patients should be instructed not to attempt to crush or split the tablet.

The tablet should not be stored once removed from the blister package as the tablet integrity can not be guaranteed and a risk of accidental exposure to a tablet can occur.

Tablet administration

Patients should remove the tablet from the blister unit and immediately place the entire Fentanyl HEXAL tablet in the buccal cavity (near a molar between the cheek and gum).

The Fentanyl HEXAL tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed.

Fentanyl HEXAL should be placed and retained within the buccal cavity for a period sufficient to allow disintegration of the tablet which usually takes approximately 14-25 minutes.

Alternatively, the tablet could be placed sublingually.

After 30 minutes, if remnants from the Fentanyl HEXAL tablet remain, they may be swallowed with a glass of water.

The length of time that the tablet takes to fully disintegrate following oromucosal administration does not appear to affect early systemic exposure to fentanyl.

Patients should not consume any food and drink when a tablet is in the buccal cavity.

In case of buccal mucosa irritation, a change in tablet placement within the buccal cavity should be recommended.

Treatment should be initiated by and remain under the supervision of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential for abuse of fentanyl.

Posology

Fentanyl HEXAL should be titrated to an “effective” dose that provides adequate analgesia and minimises adverse reactions without causing undue (or intolerable) adverse reactions, for two consecutively treated episodes of BTP. The efficacy of a given dose should be assessed over the ensuing 30 minute period.

Patients should be carefully monitored until an effective dose is reached.

Fentanyl HEXAL is available in two strengths: 100 micrograms/spray and 400 micrograms/spray.

One dose of Fentanyl HEXAL may include administration of 1 spray (100 microgram or 400 microgram doses) or 2 sprays (200 microgram or 800 microgram doses) of the same strength (either 100 microgram or 400 microgram strength).

Patients should not use more than 4 doses per day. Patients should wait at least 4 hours after a dose before treating another BTP episode with Fentanyl HEXAL.

Fentanyl HEXAL can deliver 100, 200, 400 and 800 microgram doses as follows:

Initial dose

- The initial dose of Fentanyl HEXAL to treat episodes of BTP is always 100 micrograms (one spray), even in patients switching from other fentanyl containing products for their BTP.

- Patients must wait at least 4 hours before treating another episode of BTP with Fentanyl HEXAL.

Method of titration

- Patients should be prescribed an initial titration supply of one bottle (2 sprays or 8 sprays) of Fentanyl HEXAL 100 micrograms/spray.

- Patients whose initial dose is 100 micrograms and who need to titrate to a higher dose due to a lack of effect can be instructed to use two 100 microgram sprays (one in each nostril) for their next BTP episode. If this dose is not successful, the patient may be prescribed a bottle of Fentanyl HEXAL 400 micrograms/spray and instructed to change to one 400 microgram spray for their next episode of pain. If this dose is not successful, the patient may be instructed to increase to two 400 microgram sprays (one in each nostril).

- From treatment initiation, patients should be closely followed and the dose titrated until an effective dose is reached and confirmed for two consecutively treated episodes of BTP.

Titration in patients switching between immediate-release fentanyl containing products

Substantial differences may exist in the pharmacokinetic profile of immediate-release fentanyl medicinal products, which result in clinically important differences in the rate and extent of absorption of fentanyl. Therefore, when switching between fentanyl containing medicinal products indicated for treatment of breakthrough pain, including intranasal formulations, it is essential that patients are again titrated with the new medicinal product, and not switched on a dose-for-dose (microgram-for-microgram) basis.

Maintenance therapy

Once an effective dose has been established during titration, patients should continue to take this dose up to a maximum of 4 doses per day.

Dose readjustment

Generally, the maintenance dose of Fentanyl HEXAL should be increased only where the current dose fails to adequately treat the BTP for several consecutive episodes.

A review of the dose of the background opioid therapy may be required if patients consistently present with more than four BTP episodes per 24 hours.

If adverse reactions are intolerable or persistent, the dose should be reduced or treatment with Fentanyl HEXAL replaced by another analgesic.

Discontinuation of therapy

Fentanyl HEXAL should be discontinued immediately if the patient no longer experiences breakthrough pain episodes. The treatment for persistent backgound pain should be kept as prescribed.

If discontinuation of all opioid therapy is required, the patient must be closely followed by the doctor as gradual downward opioid titration therapy is necessary in order to avoid the possibility of abrupt withdrawal effects.

Special populations

Elderly (older than 65 years)

In the Fentanyl HEXAL clinical trial programme, 104 (26.1%) of patients were over 60 years of age, 67 (16.8%) over 65 years and 15 (3.8%) over 75 years. There was no indication that older patients tended to titrate to lower doses or experience more adverse reactions. Nevertheless, in view of the importance of renal and hepatic function in the metabolism and clearance of fentanyl, additional care should be exercised in the use of Fentanyl HEXAL in the elderly. No data on the pharmacokinetics of Fentanyl HEXAL in elderly patients are available.

Hepatic or renal impairment

Fentanyl HEXAL should be administered with caution to patients with moderate or severe hepatic or renal impairment.

Paediatric population

The safety and efficacy of Fentanyl HEXAL in children and adolescents aged below 18 years have not yet been established.

No data are available.

Method of administration

Fentanyl HEXAL is for nasal use only.

The bottle should be removed from the child resistant container immediately prior to use and the protective cap removed. The bottle must be primed before first use by holding upright and simply pressing and releasing the finger grips either side of the nozzle until a green bar appears in the counting window (should occur after four sprays).

2 spray bottle:

8 spray bottle:

If the product has not been used for 5 days, it should be re-primed by spraying once.

The patient should be advised to write the date of first use in the space provided on the label of the child resistant container.

To administer Fentanyl HEXAL the nozzle is placed a short distance (about 1 cm) into the nostril and pointed slightly towards the bridge of the nose. A spray is then administered by pressing and releasing the finger grips either side of the nozzle. An audible click will be heard and the number displayed on the counter will advance by one.

Patients must be advised that they may not feel the spray being administered, and that they should, therefore, rely on the audible click and the number on the counter advancing to confirm that a spray has been delivered.

The Fentanyl HEXAL spray droplets form a gel in the nose. Patients should be advised not to blow their nose immediately after Fentanyl HEXAL administration.

The protective cap should be replaced after each use and the bottle returned to the child resistant container for safe storage.

Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.

Severe respiratory depression or severe obstructive lung conditions.

Treatment of acute pain other than breakthrough pain.

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.

Severe respiratory depression or cystic fibrosis.

-

- Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.

- Treatment of acute pain other than breakthrough pain.

- Simultaneous use of monoamine oxidase inhibitors (MAO inhibitors), or within 2 weeks after the cessation of the use of MAO inhibitors.

- Severe respiratory depression or severe obstructive lung conditions.

Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.

Severe respiratory depression or severe obstructive lung conditions.

Treatment of acute pain other than breakthrough pain

Patients without maintenance opioid therapy as there is an increased risk of respiratory depression.

Severe respiratory depression or severe obstructive lung conditions.

Treatment of acute pain other than breakthrough pain.

Patients and their carers must be instructed that Fentanyl HEXAL contains an active substance in an amount that can be fatal to a child, and therefore to keep all tablets out of the reach and sight of children.

Due to the potentially serious undesirable effects that can occur when taking an opioid therapy such as Fentanyl HEXAL, patients and their carers should be made fully aware of the importance of taking Fentanyl HEXAL correctly and what action to take should symptoms of overdose occur.

Before Fentanyl HEXAL therapy is initiated, it is important that the patient's long-acting opioid treatment used to control their persistent pain has been stabilised.

Upon repeated administration of opioids such as fentanyl, tolerance and physical and/or psychological dependence may develop. Iatrogenic addiction following therapeutic use of opioids is rare.

In common with all opioids, there is a risk of clinically significant respiratory depression associated with the use of Fentanyl HEXAL. Particular caution should be exercised during dose titration with Fentanyl HEXAL in patients with chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression (e.g. myasthenia gravis) because of the risk of further respiratory depression, which could lead to respiratory failure.

Fentanyl HEXAL should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of hyperkapnia, such as those showing evidence of raised intracranial pressure, reduced consciousness, coma or brain tumours. In patients with head injuries, the clinical course may be masked by the use of opioids. In such a case, opioids should be used only if absolutely necessary.

Cardiac disease

Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre-existing bradyarrythmias.

Data from intravenous studies with fentanyl suggest that older patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the active substance than younger patients. Older, cachectic, or debilitated patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Fentanyl HEXAL should be administered with caution to patients with liver or kidney dysfunction, especially during the titration phase. The use of Fentanyl HEXAL in patients with hepatic or renal impairment may increase the bioavailability of fentanyl and decrease its systemic clearance, which could lead to accumulation and increased and prolonged opioid effects.

Care should be taken in treating patients with hypovolaemia and hypotension.

Fentanyl HEXAL has not been studied in patients with mouth wounds or mucositis. There may be a risk of increased systemic drug exposure in such patients and therefore extra caution is recommended during dose titration.

There should be no noticeable effects on cessation of treatment with Fentanyl HEXAL, but possible symptoms of withdrawal are anxiety, tremor, sweating, paleness, nausea and vomiting.

Serotonin Syndrome

- Caution is advised when Fentanyl HEXAL is coadministered with drugs that affect the serotoninergic neurotransmitter systems.

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

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

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

Warnings:

Tolerance and dependence may occur. Following intravenous administration of Fentanyl HEXAL, a transient fall in blood pressure may occur, especially in hypovolaemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.

Respiratory Depression

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early postoperative period. Care should be taken after large doses or infusions of Fentanyl HEXAL to ensure that adequate spontaneous breathing has been established and maintained before discharging the patient from the recovery area.

Significant respiratory depression will occur following the administration of Fentanyl HEXAL in doses in excess of 200 mcg. This, and the other pharmacological effects of Fentanyl HEXAL, can be reversed by specific narcotic antagonists (e.g. naloxone). Additional doses of the latter may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist.

Resuscitation equipment and opioid antagonists should be readily available. Hyperventilation during anaesthesia may alter the patients response to CO₂, thus affecting respiration postoperatively.

Administration in labour may cause respiratory depression in the new-born infant.

Cardiac disease

Bradycardia and possibly asystole can occur if the patient has received an insufficient amount of anticholinergic, or when Fentanyl HEXAL is combined with non-vagolytic muscle relaxant. Bradycardia can be antagonised by atropine.

Muscle rigidity

Muscular rigidity (morphine-like effect) may occur.

Rigidity, which may also involve the thoracic muscles, can be avoided by the following measures:

- slow I.V. injection (usually sufficient for lower doses)

- premedication with benzodiazepines

- use of muscle relaxants.

Non-epileptic (myo)clonic movement can occur

Special dosing conditions

The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients the transient decrease in the mean arterial pressure has occasionally been accompanied by a transient reduction of the cerebral perfusion pressure.

It is wise to reduce dosage in the elderly and debilitated patients.

In uncontrolled hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and liver or renal impairment the dosage should be titrated with care and prolonged post-operative monitoring may be required.

Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.

Myasthenia gravis

In patients with myasthenia gravis, careful consideration should be applied in the use of certain anticholinergic agents and neuromuscular-blocking pharmaceutical agents prior to, and during, the administration of a general anaesthetic regimen which includes administering intravenous Fentanyl HEXAL.

Precautions:

Fentanyl HEXAL should be given only in an environment where the airway can be controlled and by personnel who can control the airway.

Interaction with neuroleptics:

If Fentanyl HEXAL is administered with a neuroleptic, the user should be familiar with the special properties of each drug, particularly the difference in duration of action. When such a combination is used, there is a higher incidence of hypotension. Neuroleptics can induce extrapyramidal symptoms that can be controlled with anti-Parkinson agents.

Bile duct:

As with other opioids, due to the anticholinergic effects, administration of Fentanyl HEXAL may lead to increases of bile duct pressure and, in isolated cases, spasms of the Sphincter of Oddi might be observed.

Serotonin Syndrome:

Caution is advised when Fentanyl HEXAL is co-administered with drugs that affect the serotonergic neurotransmitter systems.

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

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperoreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, rapid discontinuation of Fentanyl HEXAL should be considered.

Paediatric population

Techniques that involve analgesia in a spontaneous breathing child should only be used as part of an anaesthetic technique, or given as part of a sedation/analgesia technique with experienced personnel in an environment that can manage sudden chest wall rigidity requiring intubation, or apnoea requiring airway support.

Fentanyl HEXAL Injection contains 3.5 mg sodium per ml of solution, equivalent to 0.18% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

Patients who have experienced serious adverse events should be monitored for at least 24 hours after removal of Fentanyl HEXAL DTrans, 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 Fentanyl HEXAL DTrans 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.

Opioid-naïve and not opioid-tolerant states

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

Respiratory depression

Some patients may experience significant respiratory depression with Fentanyl HEXAL DTrans; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the Fentanyl HEXAL DTrans patch. The incidence of respiratory depression increases as the Fentanyl HEXAL DTrans dose is increased. Central nervous system depressants may increase the respiratory depression.

Chronic pulmonary disease

Fentanyl HEXAL DTrans 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.

Drug dependence and potential for abuse

Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids.

Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Fentanyl HEXAL DTrans may result in overdose and/or death. Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require monitoring for signs of misuse, abuse, or addiction.

Central Nervous System conditions including increased intracranial pressure

Fentanyl HEXAL DTrans 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. Fentanyl HEXAL DTrans should be used with caution in patients with brain tumours.

Cardiac disease

Fentanyl may produce bradycardia and should therefore be administered with caution to patients with bradyarrhythmias.

Hypotension

Opioids may cause hypotension, especially in patients with acute hypovolaemia. Underlying, symptomatic hypotension and/or hypovolaemia should be corrected before treatment with fentanyl transdermal patches is initiated.

Hepatic impairment

Because fentanyl is metabolised to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Fentanyl HEXAL DTrans, they should be observed carefully for signs of fentanyl toxicity and the dose of Fentanyl HEXAL DTrans reduced if necessary .

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. If patients with renal impairment receive Fentanyl HEXAL DTrans, 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.

Fever/external heat application

Fentanyl concentrations may increase if the skin temperature increases. Therefore, patients with fever should be monitored for opioid undesirable effects and the Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans application site to direct external heat sources such as heating pads, electric blankets, heated water beds, heat or tanning lamps, sunbathing, hot water bottles, prolonged hot baths, saunas and hot whirlpool spa baths.

Serotonin syndrome

Caution is advised when Fentanyl HEXAL DTrans 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 which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.

Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (eg, hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhoea).

If serotonin syndrome is suspected, treatment with Fentanyl HEXAL DTrans should be discontinued.

Interactions with other medicinal products

CYP3A4 inhibitors

The concomitant use of Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans patch. A patient who is treated with Fentanyl HEXAL DTrans should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor. If concomitant use of Fentanyl HEXAL DTrans with a CYP3A4 inhibitor cannot be avoided, close monitoring for signs or symptoms of increased or prolonged therapeutic effects and adverse effects of fentanyl (in particular respiratory depression) is warranted, and the Fentanyl HEXAL DTrans dosage must be reduced or interrupted as deemed necessary.

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.

Use in elderly patients

Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the active substance than younger patients. If elderly patients receive Fentanyl HEXAL DTrans, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Gastrointestinal tract

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Patients should be advised on measures to prevent constipation and prophylactic laxative use should be considered. Extra caution should be used in patients with chronic constipation. If paralytic ileus is present or suspected, treatment with Fentanyl HEXAL DTrans 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

Paediatric population

Fentanyl HEXAL DTrans should not be administered to opioid-naïve paediatric patients . The potential for serious or life-threatening hypoventilation exists regardless of the dose of Fentanyl HEXAL DTrans transdermal system administered.

Fentanyl HEXAL DTrans has not been studied in children under 2 years of age. Fentanyl HEXAL DTrans should be administered only to opioid-tolerant children age 2 years or older.

To guard against accidental ingestion by children, use caution when choosing the application site for Fentanyl HEXAL DTrans and monitor adhesion of the patch closely.

Before any surgery, the healthcare professional should ensure that the patient has been properly informed on how to use Fentanyl HEXAL post-operatively.

A potentially dangerous amount of fentanyl remains in the Fentanyl HEXAL system after use.

Fentanyl HEXAL should be removed before a magnetic resonance imaging (MRI) procedure, cardioversion, defibrillation, X-ray, CT scan or diathermy is undertaken.

Excessive sweating may reduce delivery of fentanyl.

Respiratory depression

Fentanyl HEXAL should only be activated by the patient, to avoid potential overdosing.

Significant respiratory depression may occur with Fentanyl HEXAL; patients must be observed for these effects.

The use of concomitant CNS-active medicinal products may increase the risk of respiratory depression.

Chronic pulmonary disease

In patients with chronic obstructive pulmonary disease or patients with conditions pre-disposing them to hypoventilation, more severe adverse reactions may be experienced. In such patients, opioids may decrease respiratory drive and increase airway resistance.

Head injuries and increased intracranial pressure

Fentanyl should not be used 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. Opioids may obscure the clinical course of patients with head injury. Fentanyl should be used with caution in patients with brain tumours or other significant space occupying lesions of the brain.

Cardiac disease

Fentanyl may produce bradycardia or hypotension and should, therefore, be administered with caution to patients with bradyarrhythmias or any significant cardiovascular disease.

Paralytic ileus

Fentanyl HEXAL should be used with caution in patients with paralytic ileus.

Abuse potential and dependence

Fentanyl has a well-known abuse potential. Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. Physicians should evaluate patients for a history of drug abuse and follow such patients closely.

Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is rare. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Fentanyl HEXAL may result in overdose and/or death.

Hepatic disease

Fentanyl is metabolised into inactive metabolites in the liver. Hepatic disease may delay elimination. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity.

Renal disease

Less than 10% of administered fentanyl is excreted unchanged by the kidney. Unlike morphine, no active fentanyl metabolites are eliminated by the kidney. Data obtained with intravenous fentanyl in patients with renal failure suggest that the volume of distribution of fentanyl may be changed by dialysis. This may affect serum concentrations. If patients with renal impairment receive Fentanyl HEXAL, they should be observed carefully for signs of fentanyl toxicity.

Elderly patients

Elderly patients should be observed carefully for adverse effects of fentanyl during Fentanyl HEXAL administration.

Obese patients

The overall adverse reaction profile for morbidly obese patients (BMI > 40) does not suggest a meaningful difference in safety compared to patients with BMI ≤ 40. However, caution is advised when prescribing Fentanyl HEXAL in morbidly obese patients because they may be at increased risk of other comorbid respiratory conditions (i.e., sleep apnoea) potentially pre-disposing them to hypoventilation or more severe adverse reactions.

Hearing impairment

Fentanyl HEXAL should be used with caution in patients with hearing impairment who might not be able to hear the audible signals from the system.

Thoracic/chest and upper abdominal surgeries

Only limited data are available in patients with thoracic/chest and upper abdominal surgeries. Fentanyl HEXAL should, therefore, be used with caution in these patients.

Physical status

The safety of Fentanyl HEXAL has not been established in patients with American Society of Anesthesiologists (ASA) physical status classification IV (i.e. patients with a severe systemic disease that is a constant threat to life).

Patients with genetic polymorphisms affecting CYP3A4 and CYP3A5

Published literature indicates potential for increased fentanyl exposure in patients with genetic polymorphisms affecting CYP3A4 and CYP3A5, with a small variability in concentrations with transdermal administration; therefore, Fentanyl HEXAL should be used with caution in these patients

Accidental use in children

Patients and their carers must be instructed that Fentanyl HEXAL contains an active substance in an amount that can be fatal to a child. Death has been reported in children who have accidentally ingested Fentanyl HEXAL.

Patients and their carers must be instructed to keep all units out of the sight and reach of children and to discard open and unopened units appropriately. An evaluation of each out-patient concerning possible accidental child exposures should be undertaken.

Maintenance opioid therapy

The product must not be given to patients without maintenance opioid therapy as there is an increased risk of respiratory depression and death. It is important that the maintenance opioid therapy used to treat the patient's persistent pain has been stabilised before Fentanyl HEXAL therapy begins and that the patient continues to be treated with the maintenance opioid therapy whilst using Fentanyl HEXAL.

Tolerance, dependence and abuse

Like for all opioids, tolerance, physical and/or psychological dependence and abuse of fentanyl may occur. However, iatrogenic addiction following therapeutic use of opioids is rare. The risk is considered low in cancer patients with breakthrough pain, but may be higher in those patients with a history of substance abuse and alcohol dependence.

All patients treated with opioids require careful monitoring for signs of abuse and addiction.

Adrenal insufficiency

Cases of adrenal insufficiency have been reported with opioid use including fentanyl lozenges, more often following greater than one month of use. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Respiratory depression

As with all opioids, there is a risk of clinically significant respiratory depression associated with the use of Fentanyl HEXAL, patients should be monitored accordingly.

Particular caution should be used when titrating Fentanyl HEXAL in patients with non-severe chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of Fentanyl HEXAL may further decrease respiratory drive to the point of respiratory failure.

Alcohol

The concomitant use of alcohol with fentanyl can produce increased depressant effects which may result in a fatal outcome.

Intracranial effects of CO₂ retention, impaired consciousness, head injury

Fentanyl HEXAL should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO₂ retention, such as those with evidence of increased intracranial pressure, or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

Bradyarrhythmias

Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre-existing bradyarrhythmias.

Hepatic or renal impairment

In addition, Fentanyl HEXAL should be administered with caution to patients with liver or kidney dysfunction. The influence of liver and renal impairment on the pharmacokinetics of the medicinal product has not been evaluated, however, when administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal disease due to alterations in metabolic clearance and plasma proteins. After administration of Fentanyl HEXAL, impaired liver and renal function may both increase the bioavailability of swallowed fentanyl and decrease its systemic clearance, which could lead to increased and prolonged opioid effects. Therefore, special care should be taken during the titration process in patients with moderate or severe hepatic or renal disease.

Hypovolaemia, hypotension

Careful consideration should be given to patients with hypovolaemia and hypotension.

Diabetic patients

Diabetic patients should be advised that the medicinal product contains dextrates (dextrates are composed of 93 % glucose monohydrate and 7 % maltodextrin. The total glucose load per dosage unit is approximately 1.89 grams per dose).

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not use this medicinal product.

Dental decay

Normal oral hygiene is recommended to reduce any potential harm to the teeth. Because Fentanyl HEXAL contains approximately 2 grams of sugar, frequent consumption increases the risk of dental decay. The occurrence of dry mouth associated with the use of opioid medicinal products may add to this risk.

Serotonin syndrome

Caution is advised when Fentanyl HEXAL is co-administered with medicinal products that affect the serotoninergic neurotransmitter systems.

The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic medicinal products such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), and with medicinal products which impair metabolism of serotonin (including monoamine oxidase inhibitors [MAO inhibitors]). This may occur within the recommended dose.

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

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

Anaphylaxis, hypersensitivity

Anaphylaxis and hypersensitivity have been reported in association with the use of oral transmucosal fentanyl products.

Paediatric population

Fentanyl HEXAL is not recommended for use in children and adolescents below 16 years due to lack of data on safety and efficacy.

Patients and their carers must be instructed that Fentanyl HEXAL contains an active substance in an amount that can be fatal, especially to a child. Therefore they must keep all tablets out of the sight and reach of children.

In order to minimise the risks of opioid-related undesirable effects and to identify the effective dose, it is imperative that patients be monitored closely by health professionals during the titration process.

It is important that the long acting opioid treatment used to treat the patient's persistent pain has been stabilised before Fentanyl HEXAL therapy begins and that the patient continues to be treated with the long acting opioid treatment whilst taking Fentanyl HEXAL.

Respiratory depression

As with all opioids, there is a risk of clinically significant respiratory depression associated with the use of fentanyl. Improper patient selection (e.g., use in patients without maintenance opioid therapy) and/or improper dosing have resulted in fatal outcome with Fentanyl HEXAL as well as with other fentanyl products.

Chronic obstructive pulmonary disease

Particular caution should be used when titrating Fentanyl HEXAL in patients with non-severe chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression, as even normally therapeutic doses of Fentanyl HEXAL may further decrease respiratory drive to the point of respiratory failure.

Increased intracranial pressure, impaired consciousness

Fentanyl HEXAL should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO₂ retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

Cardiac disease

Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre-existing bradyarrythmias.

Hepatic or renal impairment

In addition, Fentanyl HEXAL should be administered with caution to patients with hepatic or renal impairment. The influence of hepatic and renal impairment on the pharmacokinetics of the medicinal product has not been evaluated, however, when administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal impairment due to alterations in metabolic clearance and plasma proteins. After administration of Fentanyl HEXAL, impaired hepatic and renal function may both increase the bioavailability of swallowed fentanyl and decrease its systemic clearance, which could lead to increased and prolonged opioid effects. Therefore, special care should be taken during the titration process in patients with moderate or severe hepatic or renal impairment.

Careful consideration should be given to patients with hypovolaemia and hypotension.

Serotonin Syndrome

Caution is advised when Fentanyl HEXAL is coadministered with drugs that affect the serotoninergic neurotransmitter systems.

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

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

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

Tolerance, dependence

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl. However, iatrogenic addiction following therapeutic use of opioids is rare.

Controlled sodium diet

Fentanyl HEXAL 100 micrograms buccal tablets contain 10 mg sodium per tablet. Fentanyl HEXAL 200, 400, 600 and 800 micrograms buccal tablets contain 20 mg sodium per tablet.

To be taken into consideration by patients on a controlled sodium diet.

Anaphylaxis and hypersensitivity

Anaphylaxis and hypersensitivity have been reported in association with the use of oral transmucosal fentanyl products.

Patients and their carers must be instructed that Fentanyl HEXAL contains an active substance in an amount that can be fatal to a child.

In order to minimise the risks of opioid-related adverse reactions and to identify the effective dose, it is imperative that patients be monitored closely by health professionals during the titration process.

It is important that the long acting opioid treatment used to treat the patient's persistent pain has been stabilised before Fentanyl HEXAL therapy begins.

Respiratory depression

There is a risk of clinically significant respiratory depression associated with the use of fentanyl. Patients with pain who receive chronic opioid therapy develop tolerance to respiratory depression and hence the risk of respiratory depression in these patients is reduced. The use of concomitant central nervous system depressants may increase the risk of respiratory depression.

Chronic pulmonary disease

In patients with chronic obstructive pulmonary diseases, fentanyl may cause more serious adverse reactions. In these patients, opioids may decrease respiratory drive and increase airway resistance.

Increased intracranial pressure

Fentanyl HEXAL should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO₂ retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of patients with a head injury and should be used only if clinically warranted.

Cardiac disease

Fentanyl may produce bradycardia. Fentanyl HEXAL should, therefore, be used with caution in patients with previous or pre-existing bradyarrhythmias.

Impaired hepatic or renal function

In addition, Fentanyl HEXAL should be administered with caution to patients with hepatic or renal impairment. The influence of hepatic and renal impairment on the pharmacokinetics of the medicinal product has not been evaluated; however, when administered intravenously the clearance of fentanyl has been shown to be altered in hepatic and renal impairment due to alterations in metabolic clearance and plasma proteins. Therefore, special care should be taken during the titration process in patients with moderate or severe hepatic or renal impairment.

Careful consideration should be given to patients with hypovolaemia and hypotension.

Abuse potential and tolerance

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl. However, iatrogenic addiction following therapeutic use of opioids is rare.

Athletes should be informed that treatment with fentanyl could lead to positive doping tests.

Serotonin Syndrome

Caution is advised when Fentanyl HEXAL is coadministered with medicinal products that affect the serotoninergic neurotransmitter systems.

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

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

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

Route of administration

Fentanyl HEXAL is only intended for nasal use, and must not be administered by any other route. Due to physico-chemical properties of excipients included in the formulation, intravenous or intra-arterial injection must be avoided in particular.

Nasal conditions

If the patient experiences recurrent episodes of epistaxis or nasal discomfort while taking Fentanyl HEXAL, an alternative method of administration for treatment of breakthrough pain should be considered.

Fentanyl HEXAL excipients

Fentanyl HEXAL contains propylparahydroxybenzoate (E216). Propylparahydroxybenzoate may cause allergic reactions (possibly delayed) and, exceptionally, bronchospasm (if the medicinal product is not correctly administered).

No studies on the effects on the ability to drive and use machines have been performed with Fentanyl HEXAL.

However, opioid analgesics are known to impair the mental or physical ability to perform potentially hazardous tasks such as driving or operating machinery. Patients should be advised not to drive or operate machinery if they become dizzy or drowsy or experience blurred or double vision while taking Fentanyl HEXAL.

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

Where early discharge is envisaged, patients should be advised not to drive or to operate machinery for 24 hours following administration.

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

Fentanyl HEXAL DTrans 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.

Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance.

No studies of the effects on the ability to drive and use machines have been performed. However, opioid analgesics may impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, blurred or double vision while using Fentanyl HEXAL.

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.

No studies of the effects on the ability to drive and use machines have been performed. However, opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance while taking Fentanyl HEXAL and not to drive or operate machinery until they know how they react.

Opioid analgesics may impair the mental and/or physical ability required for driving or operating machinery.

Patients should be advised not to drive or operate machinery if they experience somnolence, dizziness, or visual disturbance or other adverse reactions which can impair their ability to drive or operate machinery.

Undesirable effects typical of opioids are to be expected with Fentanyl HEXAL; they tend to decrease in intensity with continued use. The most serious potential adverse reactions associated with opioid use are respiratory depression (which could lead to respiratory arrest), hypotension and shock.

The clinical trials of Fentanyl HEXAL were designed to evaluate safety and efficacy in treating patients with breakthrough cancer pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of Fentanyl HEXAL alone.

The most frequently observed adverse reactions with Fentanyl HEXAL include typical opioid adverse reactions, such as nausea, constipation, somnolence and headache.

Tabulated Summary of Adverse Reactions with Fentanyl HEXAL and/or other fentanyl-containing compounds:

The following adverse reactions have been reported with Fentanyl HEXAL and/or other fentanyl-containing compounds during clinical studies and from post-marketing experience. They are listed below by system organ class and frequency (very common > 1/10; common > 1/100 to < 1/10; uncommon >1/1,000 to <1/100; not known (cannot be estimated from available data)). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme: www.mhra.gov.uk/yellowcard

The safety of Fentanyl HEXAL IV was evaluated in 376 subjects who participated in 20 clinical trials evaluating Fentanyl HEXAL IV as an anaesthetic. These subjects took at least 1 dose of Fentanyl HEXAL IV and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (> 5% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): nausea (26.1); vomiting (18.6); muscle rigidity (10.4); hypotension (8.8); hypertension (8.8); bradycardia (6.1) and sedation (5.3).

Including the above-mentioned ADRs, Table 1 displays ADRs that have been reported with the use of Fentanyl HEXAL IV from either clinical trials or postmarketing experience.

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 <1,1000); very rare (<10,000); and not known (cannot be estimated from the available clinical trial data).

Table 1: Adverse Drug Reactions

When a neuroleptic is used with Fentanyl HEXAL the following adverse reactions may be observed: chills and/or shivering, restlessness, postoperative hallucinatory episodes and extrapyramidal symptoms.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

The safety of Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans and provided safety data. Based on pooled safety data from these clinical studies, the most commonly reported (ie >10% incidence) adverse reactions were: nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).

The adverse reactions reported with the use of Fentanyl HEXAL DTrans from these clinical studies including the above-mentioned adverse reactions, and from post-marketing experiences are listed below in Table 5.

The displayed frequency categories use the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available clinical data). The adverse reactions are presented by System Organ Class and in order of decreasing seriousness within each frequency category.

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

Paediatric population

The safety of Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans and provided safety data.

The safety profile in children and adolescents treated with Fentanyl HEXAL DTrans was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with Fentanyl HEXAL DTrans use in children as young as 2 years old when used as directed.

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

Tolerance, physical dependence, and psychological dependence can develop on repeated use of Fentanyl HEXAL DTrans.

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to Fentanyl HEXAL DTrans or if therapy is stopped suddenly.

There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used Fentanyl HEXAL DTrans during pregnancy.

Cases of serotonin syndrome have been reported when fentanyl was administered concomitantly with highly serotonergic drugs.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

The most commonly reported adverse reactions were nausea, vomiting, and application site reactions such as erythema and pruritus. These were mostly of mild to moderate severity. The most serious adverse reactions reported were hypotension and apnoea and all patients should be closely monitored for these.

Tabulated list of adverse reactions

The following adverse reactions have been reported with Fentanyl HEXAL during clinical studies and post marketing experience. All adverse reactions are listed by System Organ Class and frequency: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); and rare (>1/10,000 to <1/1,000).

Paediatric population

Data on Fentanyl HEXAL in paediatrics is limited to information from a single clinical trial. In this study 28 paediatric patients, 6 to 16 years old, were treated with Fentanyl HEXAL fentanyl 40 micrograms after experiencing inadequate analgesia with Fentanyl HEXAL fentanyl 25 micrograms. Among these patients, the incidence of nausea was similar to adult patients; however, vomiting (32.1%) and fever (60.7%) were each reported at a higher incidence in paediatric patients relative to adults. In summary, the limited size of the overall paediatric exposure is insufficient to guide safe and effective dosing of Fentanyl HEXAL in patients younger than 18 years of age.

Elderly population

Elderly patients (> 65 years) made up 28% (499/1763) of the total controlled clinical trial exposure to Fentanyl HEXAL 40 micrograms, with approximately 10% (174/1763) of exposures being in patients > 75 years. No overall differences were observed in the safety of Fentanyl HEXAL fentanyl 40 micrograms in elderly patients (> 65 years including a subpopulation > 75 years) and adult patients for all controlled studies. Thus, the adverse reaction profile does not suggest a meaningful difference in safety compared to patients younger than 65 years of age.

Obese patients

In the controlled clinical trial population, the adverse reaction profile in patients with BMI > 40 (86/1436 or 6%) showed no meaningful difference relative to patients with BMI ≤ 40. However, caution is recommended in these patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Typical opioid adverse reactions are to be expected with Fentanyl HEXAL. Frequently, these will cease or decrease in intensity with continued use of the product, as the patient is titrated to the most appropriate dose. However, the most serious adverse events are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be closely monitored for these.

Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported in post-marketing use.

Because the clinical trials of Fentanyl HEXAL were designed to evaluate safety and efficacy in treating breakthrough pain, all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent pain. Thus it is not possible to definitively separate the effects of Fentanyl HEXAL alone.

The following adverse reactions have been reported with Fentanyl HEXAL and/or other fentanyl-containing compounds during clinical studies and post marketing experience. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: very common > 1/10, common > 1/100 to < 1/10, uncommon > 1/1,000 to < 1/100, not known (cannot be estimated from the available data):

* opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

Typical opioid adverse reactions are to be expected with Fentanyl HEXAL. Frequently, these will cease or decrease in intensity with continued use of the medicinal product, as the patient is titrated to the most appropriate dose. However, the most serious adverse reactions are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be closely monitored for these.

The clinical studies of Fentanyl HEXAL were designed to evaluate safety and efficacy in treating BTP and all patients were also taking concomitant opioids, such as sustained-release morphine or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of Fentanyl HEXAL alone.

Tabulated list of adverse reactions

The following adverse reactions have been reported with Fentanyl HEXAL and/or other fentanyl-containing compounds during clinical studies and post marketing experience. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: very common >1/10, common >1/100 to <1/10, uncommon > 1/1,000 to <1/100, rare (>1/10,000 to <1/1,000), not known (cannot be estimated from the available data); within each frequency group, undesirable effects are presented in order of decreasing seriousness:

Description of selected adverse reactions

Tolerance, physical and/or psychological dependence may develop upon repeated administration of opioids such as fentanyl.

Opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor and sweating have been observed with transmucosal fentanyl.

Loss of consciousness and respiratory arrest have been observed in the context of overdose.

Hypersensitivity reactions have been reported in post-marketing experience, including rash, erythema, lip and face swelling, and urticaria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

Typical opioid adverse reactions are to be expected with Fentanyl HEXAL. Frequently, these will cease or decrease in intensity with continued use of the medicinal product, as the patient is titrated to the most appropriate dose. However, the most serious adverse reactions are respiratory depression (potentially leading to apnoea or respiratory arrest), circulatory depression, hypotension and shock and all patients should be monitored for these.

The clinical studies of Fentanyl HEXAL were designed to evaluate safety and efficacy in treating BTP and all patients were also on background opioid therapies, such as sustained-release morphine or transdermal fentanyl, for their persistent pain. Therefore it is not possible to definitively separate the effects of Fentanyl HEXAL alone.

Tabulated list of adverse reactions

The following adverse reactions have been reported with Fentanyl HEXAL and/or other fentanyl-containing compounds during clinical studies and post marketing experience (frequencies defined as 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); unknown (cannot be estimated from available data)).

*See next section below

Description of selected adverse reactions

Opioid withdrawal symptoms such as nausea, vomiting, diarrhoea, anxiety, chills, tremor, and sweating have been observed with transmucosal fentanyl.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

The symptoms of fentanyl overdose are an extension of its pharmacological actions, the most serious effect being respiratory depression, which may lead to respiratory arrest.

Management of opioid overdose in the immediate term includes removal of any remaining Fentanyl HEXAL sublingual tablets from the mouth, physical and verbal stimulation of the patient and an assessment of the level of consciousness. A patent airway should be established and maintained. If necessary an oropharyngeal airway or endotracheal tube should be inserted, oxygen administered and mechanical ventilation initiated, as appropriate. Adequate body temperature and parenteral fluid intake should be maintained.

For the treatment of accidental overdose in opioid-naïve individuals, naloxone or other opioid antagonists should be used as clinically indicated and in accordance with their Summary of Product Characteristics. Repeated administration of the opioid antagonist may be necessary if the duration of respiratory depression is prolonged.

Care should be taken when using naloxone or other opioid antagonists to treat overdose in opioid-maintained patients, due to the risk of precipitating an acute withdrawal syndrome.

If severe or persistent hypotension occurs, hypovolaemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.

Muscle rigidity interfering with respiration has been reported with fentanyl and other opioids. In this situation, endotracheal intubation, assisted ventilation and administration of opioid antagonists as well as muscle relaxants may be requested.

Symptoms and signs:

The manifestations of Fentanyl HEXAL overdosage are generally an extension of its pharmacological action. Depending on the individual sensitivity, the clinical picture is determined by the degree of respiratory depression, which varies from bradypnoea to apnoea.

Treatment:

The patient should be carefully observed; body warmth and adequate fluid intake should be maintained. If hypotension is severe or if it persists, the possibility of hypovolaemia should be considered and, if present, it should be controlled with appropriate parenteral fluid administration.

Symptoms and signs

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

Treatment

For management of respiratory depression, immediate countermeasures include removing the Fentanyl HEXAL DTrans 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.

Symptoms

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

Treatment

For management of respiratory depression, immediate countermeasures include removing the Fentanyl HEXAL system and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone, based on the clinical judgment of the treating health care professional. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. The half-life of the antagonist may be short; therefore, repeated administration or infusion of the antagonist may be necessary. Reversal of the narcotic effect may also 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. Oxygen should be administered and respiration assisted or controlled, as appropriate. Adequate body temperature and fluid intake should also be maintained.

If severe or persistent hypotension occurs, hypovolaemia should be considered and the condition should be managed with appropriate parenteral fluid therapy or other interventions as needed, based upon the clinical judgment of the treating health care professional.

Symptoms

The symptoms of fentanyl overdose are expected to be similar in nature to those of intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant effects being altered mental status, loss of consciousness, coma, cardiorespiratory arrest, respiratory depression, respiratory distress, and respiratory failure, which have resulted in death.

Management

Immediate management of opioid overdose includes removal of the Fentanyl HEXAL unit via the applicator, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory status, and assisted ventilation (ventilatory support) if necessary.

Overdose (accidental ingestion) in the opioid naive person

For treatment of overdose (accidental ingestion) in the opioid naive person, intravenous access should be obtained, and naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the Summary of Product Characteristics of the individual opioid antagonist for details about such use.

Overdose in opioid-maintained patients

For treatment of overdose in opioid-maintained patients, intravenous access should be obtained. The judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.

Although muscle rigidity interfering with respiration has not been seen following the use of Fentanyl HEXAL, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

Symptoms

The symptoms of fentanyl overdose are expected to be similar in nature to those of intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant effects being altered mental status, loss of consciousness, hypotension, respiratory depression, respiratory distress, and respiratory failure, which have resulted in death.

Management

Immediate management of opioid overdose includes removal of the Fentanyl HEXAL buccal tablet, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory status, and assisted ventilation (ventilatory support) if necessary.

Overdose (accidental ingestion) in the opioid-naive person

For treatment of overdose (accidental ingestion) in the opioid-naive person, intravenous access should be obtained and naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the Summary of Product Characteristics of the individual opioid antagonist for details about such use.

Overdose in opioid-maintained patients

For treatment of overdose in opioid-maintained patients, intravenous access should be obtained. The judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.

Although muscle rigidity interfering with respiration has not been seen following the use of Fentanyl HEXAL, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

The symptoms of fentanyl overdose via the nasal route are expected to be similar in nature to those of intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant effect being respiratory depression.

Immediate management of opioid overdose includes ensuring a patent airway, physical and verbal stimulation of the patient, assessment of the level of consciousness, ventilatory and circulatory status, and assisted ventilation (ventilatory support) if necessary.

For treatment of overdose (accidental ingestion) in the opioid-naïve person, intravenous access should be obtained and naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g. the half life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. For details about such use the Summary of Product Characteristics of the individual opioid antagonist should be consulted.

For treatment of overdose in opioid-maintained patients, intravenous access should be obtained. The judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.

It should be noted that although statistically significant increases in C_max levels were seen following a second dose of Fentanyl HEXAL given either one or two hours after the initial dose, this increase is not considered to be large enough to suggest that clinically concerning accumulation or over-exposure would occur, providing a wide safety margin for the recommended dose interval of four hours.

Although muscle rigidity interfering with respiration has not been seen following the use of Fentanyl HEXAL, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent.

Pharmacotherapeutic group: Analgesics; Opioids; Phenylpiperidine derivatives.

ATC code: N02AB03

Fentanyl is a potent µ-opioid analgesic with rapid onset of analgesia and short duration of action. Fentanyl is approximately 100-fold more potent than morphine as an analgesic. Secondary effects of fentanyl on central nervous system (CNS), respiratory and gastro-intestinal function are typical of opioid analgesics and are considered to be class effects. These can include respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.

The analgesic effects of fentanyl are related to the blood level of the active substance; in opioid-naïve patients, minimum effective analgesic serum concentrations of fentanyl range from 0.3-1.2 ng/ml, while blood levels of 10-20 ng/ml produce surgical anaesthesia and profound respiratory depression.

In patients with chronic cancer pain on stable maintenance doses of opioids, statistically significant improvement in pain intensity difference was seen with Fentanyl HEXAL versus placebo from 10 minutes after administration onwards (see figure 1 below), with a significantly lower need for rescue analgesic therapy.

Figure 1 Mean Pain Intensity Difference from baseline (± SE) for Fentanyl HEXAL Compared with Placebo (measured by a 0-10 Likert scale)

The safety and efficacy of Fentanyl HEXAL have been evaluated in patients taking the drug at the onset of the breakthrough pain episode. Pre-emptive use of Fentanyl HEXAL for predictable pain episodes was not investigated in the clinical trials.

Fentanyl, in common with all µ-opioid receptor agonists, produces dose dependent respiratory depression. This risk is higher in opioid-naïve subjects than in patients experiencing severe pain or receiving chronic opioid therapy. Long-term treatment with opioids typically leads to development of tolerance to their secondary effects.

While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract leading to a prolongation in gastrointestinal transit time, which may be responsible for the constipating effect of fentanyl.

Pharmacotherapeutic group: Anaesthetic general, opioid anaesthetic.

ATC code: N01AH01

Fentanyl HEXAL is a synthetic opiate with a clinical potency of 50 to 100 times that of morphine. Its onset of action is rapid and its duration of action is short. In man, a single IV dose of 0.5-1 mg/70 kg body weight immediately produces a pronounced state of surgical anaesthesia, respiratory depression, bradycardia and other typical morphine-like effects. The duration of action of the peak effects about 30 minutes. All potent morphine-like drugs produce relief from pain, ventilatory depression, emesis, constipation, physical dependence, certain vagal effects and varying degrees of sedation. Fentanyl HEXAL, however, differs from morphine not only by its short duration of action but also by its lack of emetic effect and minimal hypotensive activity in animals.

Pharmacotherapeutic group: Analgesics, Opioids: phenylpiperidine derivatives,

ATC code: N02AB03

Mechanism of action

Fentanyl is an opioid analgesic, interacting predominantly with the µ opioid receptor. Its primary therapeutic actions are analgesia and sedation.

Paediatric population

The safety of Fentanyl HEXAL DTrans was evaluated in 3 open-label studies in 289 paediatric subjects with chronic pain, aged 2 to 17 years, inclusive. Eighty of the children were aged 2 to 6 years, inclusive. Of the 289 subjects enrolled in these 3 studies, 110 initiated Fentanyl HEXAL DTrans 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 subjects, 174 (97.2%) of whom had been on opioid doses of at least 45 mg of oral morphine equivalents per day. Among the remaining 5 subjects with a starting dosage of at least 25 mcg/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 mg of oral morphine equivalents per day.

Pharmacotherapeutic group: Analgesics; phenylpiperidine derivatives; ATC code: N02AB03.

Mechanism of action

Fentanyl is an opioid analgesic, interacting predominantly with the opioid μ-receptor.

Pharmacodynamic effects

Its primary therapeutic actions are analgesia and sedation. Its secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.

Clinical efficacy and safety

The efficacy and safety of Fentanyl HEXAL for treatment of acute, moderate to severe postoperative pain was evaluated in seven controlled studies in 1763 Fentanyl HEXAL patients: three placebo-controlled studies and four active-controlled studies. The placebo-controlled trials included 791 patients that were predominantly female (72%), Caucasian (82%), with a mean age of 45-54 years (range, 18-90 years), and primarily comprised of surgeries including lower abdominal (including pelvic) and orthopedic bone procedures. Patients were enrolled shortly after major surgery if they were not opioid tolerant, were expected to have an uncomplicated recovery, and required at least 24 hours of parenteral opioid treatment. Long-lasting or any non-opioid analgesics were not permitted. Patients were initially titrated to comfort with intravenous fentanyl or morphine, at which point they were randomized to Fentanyl HEXAL or a matching placebo system. During the first 3 hours post-enrollment, patients could supplement with bolus intravenous fentanyl given, as needed, to achieve comfort. After this point 727 patients remained in the studies using only the Fentanyl HEXAL or control system, and were evaluated for efficacy.

The primary endpoint in each placebo-controlled study was the proportion of withdrawals due to inadequate analgesia during the period from 3 to 24-hours after Fentanyl HEXAL application. As illustrated in Table 1 below, Fentanyl HEXAL (fentanyl hydrochloride) was superior to placebo in all studies. Additional analyses suggest that the surgical procedure type did not influence the trends in efficacy endpoints and the efficacy of Fentanyl HEXAL was similar across the range of body mass indices studied (< 25 to > 40 kg/m² Body Mass Index).

Fentanyl HEXAL was also evaluated in four active-control trials (predominantly female (65%), Caucasian (85%), with a mean age of 55 years (range, 18-91 years), and primarily comprised of surgeries including lower abdominal and orthopedic bone procedures) using a standard intravenous patient controlled analgesia (PCA) morphine regimen as the comparator. In these studies, 1313 patients undergoing major surgery were randomized to PCA with intravenous morphine (1 mg morphine bolus, 5 minute lock-out, total of 10 mg/h) delivered by a pump, and 1288 patients were randomized to Fentanyl HEXAL. Similar to the placebo-controlled studies, in the immediate postoperative period, patients were titrated to comfort with intravenous fentanyl or morphine per hospital protocol. Once comfortable, patients were then randomized to either Fentanyl HEXAL or intravenous PCA morphine treatment. Patients were instructed to use the system for pain relief.

These studies evaluated Fentanyl HEXAL vs. intravenous PCA morphine in various surgical procedures commonly seen in clinical practice. Study C-2000-007 evaluated patients after undergoing abdominal, thoracic, or orthopedic surgeries; Study CAPSS-319 evaluated patients after undergoing total hip replacement; Study CAPSS-320 assessed Fentanyl HEXAL in patients following abdominal and pelvic surgeries; and Study FEN-PPA-401 assessed patients following major abdominal or orthopedic surgery. Patients could remain in their respective study up to 72 hours if they required parenteral opioid analgesia for this duration. A new Fentanyl HEXAL system was applied every 24 hours to different skin sites, or earlier if all doses were used. Supplemental intravenous opioid medication (fentanyl or morphine) was only allowed during the first 3 hours of Fentanyl HEXAL or PCA morphine treatment. Concomitant use of analgesics was not allowed after 3 hours in Studies C-2000-007 and CAPSS-320. In Study CAPSS-319, half the patients in each group received rofecoxib perioperatively and in Study FEN-PPA-401 patients were allowed non-opioid analgesics throughout the study period. The primary efficacy endpoint was the patient global assessment of method of pain control at 24 hours used to test equivalence between Fentanyl HEXAL and intravenous PCA morphine using a pre-specified ± 10% equivalence boundary with a 2-sided 95% confidence interval. Each patient and investigator was asked to rate the patient's method of pain control as either poor, fair, good, or excellent. Efficacy results at the end of 24 hours, are presented in Table 2 below for the evaluable patient population. As shown below, the primary endpoint, proportion of patients reporting “Good or Excellent” ratings for the two methods of pain relief in all four studies demonstrated equivalence, with each 95% confidence interval contained within the prespecified ± 10% equivalence boundaries.

Table 2

Active Comparator Trials (n=2569) Evaluable Patients

^a 95% Confidence Interval for difference in proportions

^b The pre-specified equivalence boundary was ± 10%

Across the active-controlled studies, dosing with Fentanyl HEXAL was similar to intravenous PCA morphine pump use. The mean amount of supplemental opioid used during this time was also similar among patients treated with Fentanyl HEXAL or PCA morphine i.e. a range across the 4 studies of a mean dose of 5.0 - 7.5 mg morphine in patients treated with Fentanyl HEXAL compared to a mean dose of 5.4 - 7.7mg morphine in patients receiving PCA morphine.. Patients who completed 24 hours of Fentanyl HEXAL treatment in the seven controlled studies used a wide range of the available 80 doses, with a mean of 29.0 doses/patient (range of 0-93 doses) with the majority of patients (56.5%) using between 11 to 50 doses. A single Fentanyl HEXAL system provided a sufficient number of doses for 99% of the studied patients over 24 hours.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Fentanyl HEXAL in one or more subsets of the paediatric population for the treatment of acute pain.

Pharmacotherapeutic group: Opioid analgesic, phenylpiperidone derivative. ATC code: N02AB03.

Fentanyl, a pure opioid agonist, acts primarily through interaction with mu-opioid receptors located in the brain, spinal cord and smooth muscle. The primary site of therapeutic action is the central nervous system (CNS). The most clinically useful pharmacological effect of the interaction of fentanyl with mu-opioid receptors is analgesia. The analgesic effects of fentanyl are related to the blood level of the active substance, if proper allowance is made for the delay into and out of the CNS (a process with a 3-5 minute half-life). In opioid-naïve individuals, analgesia occurs at blood levels of 1 to 2 ng/ml, while blood levels of 10-20 ng/ml would produce surgical anaesthesia and profound respiratory depression.

In patients with chronic cancer pain on stable doses of regularly scheduled opioids to control their persistent pain, Fentanyl HEXAL produced significantly more breakthrough pain relief compared with placebo at 15, 30, 45, and 60 minutes following administration.

Secondary actions include increase in the tone and decrease in the contractions of the gastrointestinal smooth muscle, which results in prolongation of gastrointestinal transit time and may be responsible for the constipatory effect of opioids.

While opioids generally increase the tone of urinary tract smooth muscle, the overall effect tends to vary, in some cases producing urinary urgency, in others difficulty in urination.

All opioid mu-receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory depression is less in patients with pain and those receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects. In non-tolerant subjects, typically peak respiratory effects are seen 15 to 30 minutes following the administration of Fentanyl HEXAL, and may persist for several hours.

Additional secondary pharmacological effect includes miosis.

Paediatric population

There is limited experience of the use of Fentanyl HEXAL in paediatric patients, below the age of 16. In a clinical study, 15 (out of 38) paediatric patients, ranging in age from 5 to 15 years, already receiving maintenance opioid therapy and with breakthrough pain were treated with Fentanyl HEXAL. The study was too small to allow conclusions on safety and efficacy in this patient population.

Pharmacotherapeutic group: analgesics; opioids; ATC code N02AB03.

Mechanism of action and pharmacodynamic effects

Fentanyl is an opioid analgesic, interacting predominantly with the opioid µ-receptor. Its primary therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.

The analgesic effects of fentanyl are related to its plasma level. In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance to opioids. The rate of development of tolerance varies widely among individuals. As a result, the dose of Fentanyl HEXAL should be individually titrated to achieve the desired effect.

All opioid µ-receptor agonists, including fentanyl, produce dose dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy as these patients will develop tolerance to respiratory depressant effects.

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes.).

Clinical efficacy and safety

The safety and efficacy of Fentanyl HEXAL have been evaluated in patients taking the drug at the onset of the breakthrough pain episode. Pre-emptive use of Fentanyl HEXAL for predictable pain episodes was not investigated in the clinical trials. Two double-blind, randomized, placebo-controlled crossover studies have been conducted involving a total of 248 patients with BTP and cancer who experienced on average 1 to 4 episodes of BTP per day while taking maintenance opioid therapy. During an initial open-label phase, patients were titrated to an effective dose of Fentanyl HEXAL. Patients who identified an effective dose entered the double-blind phase of the study. The primary efficacy variable was the patient's assessment of pain intensity. Patients assessed pain intensity on a 11-point scale. For each BTP episode, pain intensity was assessed prior to and at several time points after treatment.

Sixty-seven percent of the patients were able to be titrated to an effective dose.

In the pivotal clinical study (study 1), the primary endpoint was the average sum of differences in pain intensity scores from dosing to 60 minutes, inclusive (SPID60), which was statistically significant compared to placebo (p<0.0001).

In the second pivotal study (study 2), the primary endpoint was SPID30, which was also statistically significant compared to placebo (p<0.0001).

Statistically significant improvement in pain intensity difference was seen with Fentanyl HEXAL versus placebo as early as 10 minutes in Study 1 and as early as 15 minutes (earliest time point measured) in Study 2. These differences continued to be significant at each subsequent time point in each individual study.

Pharmacotherapeutic group: Analgesics; opioids; phenylpiperidine derivatives;

ATC code: N02AB03.

Mechanism of action

Fentanyl is an opioid analgesic, interacting predominantly with the opioid µ-receptor. Its primary therapeutic actions are analgesia and sedation. Secondary pharmacological effects are respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and euphoria.

Pharmacodynamic effects

A double-blind, randomised, placebo-controlled crossover study has been conducted in which 114 patients who experienced on average 1 to 4 episodes of break through pain (BTP) per day while taking maintenance opioid therapy were entered into an initial open-label titration phase in order to identify an effective dose of Fentanyl HEXAL (Study CP043). The patients entering the double-blind phase treated up to 10 episodes of BTP with either Fentanyl HEXAL (7 episodes) or placebo (3 episodes) in a random order.

Of the patients entering the titration phase, only 7 (6.1 %) were unable to be titrated to an effective dose due to lack of efficacy and 6 (5.3 %) withdrew due to adverse events.

The primary endpoint was the comparison between the summed pain intensity difference at 30 minutes after dosing (SPID₃₀), which was 6.57 in the Fentanyl HEXAL-treated episodes compared to 4.45 for placebo (p<0.0001 ). The SPID for Fentanyl HEXAL-treated episodes was also significantly different to placebo at 10 15, 45 and 60 minutes after administration.

The mean pain intensity scores (73 patients) for all Fentanyl HEXAL-treated episodes (459 episodes) compared to those treated with placebo (200 episodes) were significantly lower at 5, 10, 15, 30, 45 and 60 minutes following administration (see Figure 1).

Figure 1: Mean (± SE) Pain Intensity Scores at Each Time Point (mITT Population)

The superior efficacy of Fentanyl HEXAL over placebo was supported by data from secondary endpoints including the number of BTP episodes with clinically meaningful pain relief, defined as a reduction in pain intensity score of at least 2 (Figure 2).

Figure 2: Clinically Meaningful Pain Relief - Fentanyl HEXAL vs placebo: % Patients' Episodes With >2 Point Reduction in Pain Intensity

In a double-blind, randomized comparator-controlled study (Study 044) of similar design to Study 043 conducted in opioid-tolerant patients with breakthrough cancer pain on stable doses of regularly scheduled opioids, Fentanyl HEXAL was shown to be superior to immediate-release morphine sulfate (IRMS). Superiority was demonstrated by the primary endpoint, Pain Intensity Difference within 15 minutes, which was 3.02 in patients treated with Fentanyl HEXAL compared to 2.69 in patients treated with IRMS (p=0.0396).

In a long-term, open-label, safety study (Study 045), 355 patients entered the 16-week treatment phase, during which 42,227 episodes of breakthrough cancer pain (BTP) were treated with Fentanyl HEXAL. One hundred of these patients continued treatment for up to 26 months in an extension phase. Of the 355 patients treated in the open-label treatment phase, 90 % required no increase in dose.

In the randomised, placebo-controlled study (CP043) 9.4% of 459 Fentanyl HEXAL-treated BTP episodes in 73 patients required use of any further (rescue) medicinal products within 60 minutes of dosing. During the longer-term, open-label study (CP045) this was 6.0 % of 42,227 episodes in 355 patients treated with Fentanyl HEXAL during up to 159 days of treatment.

Fentanyl is a highly lipophilic drug absorbed very rapidly through the oral mucosa and more slowly through the gastrointestinal tract. Orally administered fentanyl undergoes pronounced hepatic and intestinal first pass effects.

Fentanyl HEXAL is a quick dissolving sublingual tablet formulation. Rapid absorption of fentanyl occurs over about 30 minutes following administration of Fentanyl HEXAL. The absolute bioavailability of Fentanyl HEXAL has been calculated to be 54 %. Mean maximal plasma concentrations of fentanyl range from 0.2 to 1.3 ng/ml (after administration of 100 to 800 µg Fentanyl HEXAL) and are reached within 22.5 to 240 minutes.

About 80-85% of fentanyl is bound by plasma proteins, mainly α1-glycoprotein and to a lesser extent albumin and lipoprotein. The volume of distribution of fentanyl at steady state is about 3-6 l/kg.

Fentanyl is metabolised primarily via CYP3A4 to a number of pharmacologically inactive metabolites, including norfentanyl. Within 72 hours of intravenous fentanyl administration around 75% of the dose is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of the dose is recovered in the faeces, primarily as metabolites. Total plasma clearance of fentanyl is about 0.5 l/h/kg.

After Fentanyl HEXAL administration, the main elimination half-life of fentanyl is about 7 hours (range 3-12.5 hours) and the terminal half-life is about 20 hours (range 11.5-25 hours).

The pharmacokinetics of Fentanyl HEXAL have been shown to be dose proportional over the dose range of 100 to 800 µg. Pharmacokinetic studies have shown that multiple tablets are bioequivalent to single tablets of the equivalent dose.

Renal/hepatic impairment

Impaired hepatic or renal function could cause increased serum concentrations. Older, cachectic or generally impaired patients may have a lower fentanyl clearance, which could cause a longer terminal half-life for the compound.

Some pharmacokinetic parameters for Fentanyl HEXAL are as follows:

Urinary excretion = 8%

Bound in plasma = 80%

Clearance (ml/min/kg) = 13±2

Volume of distribution (litres/kg) = 4.0±0.4

Estimates of terminal half-life range from 141 to 853 minutes.

Renal impairment

Data obtained from a study administering IV Fentanyl HEXAL in patients undergoing renal transplantation suggest that the clearance of Fentanyl HEXAL may be reduced in this patient population.).

Obese Patients

An increase in clearance of Fentanyl HEXAL is observed with increased body weight. In patients with a BMI >30, clearance of Fentanyl HEXAL increases by approximately 10% per 10 kg increase of the fat free mass (lean body mass).

Absorption

Fentanyl HEXAL DTrans provides continuous systemic delivery of fentanyl during the 72-hour application period. Following Fentanyl HEXAL DTrans 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 Fentanyl HEXAL DTrans application, serum fentanyl concentrations increase gradually, generally leveling 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. High inter-subject variability in plasma concentrations has been observed.

A pharmacokinetic model has suggested that serum fentanyl concentrations may increase by 14% (range 0-26%) if a new patch is applied after 24 hours rather than the recommended 72-hour application.

Skin temperature elevation may enhance the absorption of transdermally-applied fentanyl. An increase in skin temperature through the application of a heating pad on low setting over the Fentanyl HEXAL DTrans 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, norfentanyl, 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 systemic circulation.

Elimination

Following a 72-hour patch application, the mean fentanyl half-life 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 Fentanyl HEXAL DTrans patch size. The pharmacokinetics of transdermal fentanyl do not change with repeated application.

Pharmacokinetic/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 Fentanyl HEXAL DTrans, healthy elderly subjects had fentanyl pharmacokinetics which did not differ significantly from healthy young subjects although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary .

Renal impairment

The influence of renal impairment on 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.

Hepatic impairment

Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of Fentanyl HEXAL DTrans should be reduced if necessary. 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 accumulates 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 when compared to children 11 to 16 years old, who are expected to have a similar clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.

Absorption

At the initiation of each dose, an electrical current moves a pre-determined amount of fentanyl from the active substance-containing reservoir through the skin and into systemic circulation. Fentanyl HEXAL delivers a nominal dose of 40 micrograms fentanyl over each 10-minute dosing period at steady state. The mean systemic bioavailability is 87%. Upon system removal after the last dose, the decline in serum fentanyl concentration is similar to that of intravenous fentanyl.

Absorption of fentanyl from Fentanyl HEXAL is similar whether applied to the upper outer arm or chest. When the system is applied on the lower inner arm, the amount of fentanyl absorbed is approximately 20% lower than at the upper outer arm or chest. Fentanyl pharmacokinetics are similar with both single and multiple 24 hour applications.

Systemic absorption of fentanyl increases as a function of time independent of the frequency of dosing, with the initial dose being approximately 16 micrograms. Steady state absorption of the nominal 40 microgram dose is achieved about 12 hours after application, indicating that the skin becomes more permeable to fentanyl during the first 12 hours. The pharmacokinetic absorption profile will repeat with each application to a new skin site, therefore with each new application, absorption will be lower initially. Consequently, the patient may activate Fentanyl HEXAL more frequently to maintain fentanyl blood levels.

When Fentanyl HEXAL is applied without activating the electrical current, the average absorption rate of fentanyl over 24 hours was 2.3 micrograms fentanyl/hour, indicating minimal passive delivery.

Average serum concentrations observed in post-surgical patients were in the range of 0.4-1.5 ng/ml over a 24 hour dosing period. In general, the maximum serum fentanyl concentration occurs approximately 15 minutes after the initiation of a dose.

Following an on-demand dose of fentanyl by Fentanyl HEXAL, fentanyl has an absorption half-life of approximately 15 minutes.

Distribution

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. Fentanyl exhibits three compartment distribution pharmacokinetics. With intravenous administration, the initial distribution half-life is approximately 6 minutes; the second distribution half-life is 1 hour, and the terminal half-life is 13 hours. The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

The average volume of distribution for fentanyl at steady state is 6 L/kg, the average clearance is 53 L/h.

Biotransformation

Fentanyl is metabolised primarily in the liver to norfentanyl by CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. More than 90% of the administered dose of fentanyl is eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Skin does not appear to metabolise fentanyl delivered transdermally.

Elimination

Around 75% of fentanyl is excreted into the urine, mostly as metabolites, with less than 10% as unchanged active substance. About 9% of the dose is recovered in the faeces, primarily as metabolites. The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h

Linearity/non-linearity

Dose proportionality has been demonstrated from 25 to 60 micrograms per dose.

None of the four demographic factors studied [weight (lean/obese), age, race, or gender] had a significant effect on active substance exposure (AUC) following use of Fentanyl HEXAL.

Pharmacokinetic /pharmacodynamic relationship

Minimum effective analgesic serum concentrations of fentanyl in opioid-naïve patients treated for acute post-operative pain range from 0.2 to 1.2 ng/ml; undesirable effects increase in frequency at serum levels above 2 ng/ml.

Patients with genetic polymorphisms affecting CYP3A4 and CYP3A5

Published literature has indicated that the CYP3A4*22 and CYP3A5*3 single nucleotide polymorphisms influence fentanyl to norfentanyl metabolism with the potential for increased fentanyl exposure in patients with these genetic polymorphs. Literature has shown that the genetic polymorphisms only account for a small amount of variability in concentrations of fentanyl with transdermal administration. Another published article of 52 elderly Japanese post-operative patients receiving continuous intravenous (IV) fentanyl infusion (0.5-1.5 µg/kg/h) showed increased fentanyl exposure in the CYP3A5*3 group (3*/3*) than in the 1* carrier group. Clinical relevance is unknown from these published articles; however, caution should be used if administering Fentanyl HEXAL in patients with genetic polymorphisms of CYP3A4 and CYP3A5.

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the oral mucosa and more slowly by the conventional gastrointestinal route. It is subject to first-pass hepatic and intestinal metabolism and the metabolites do not contribute to fentanyl's therapeutic effects.

Absorption

The absorption pharmacokinetics of fentanyl from Fentanyl HEXAL are a combination of rapid oromucosal absorption and slower gastrointestinal absorption of swallowed fentanyl. Approximately 25 % of the total dose of Fentanyl HEXAL is rapidly absorbed from the buccal mucosa. The remaining 75 % of the dose is swallowed and slowly absorbed from the gastrointestinal tract. About 1/3 of this amount (25 % of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Absolute bioavailability is about 50 % compared to intravenous fentanyl, divided equally between rapid oromucosal and slower gastrointestinal absorption. C_max ranges from 0.39 to 2.51 ng/mL after consumption of Fentanyl HEXAL (200 micrograms to 1,600 micrograms). T_max is around 20 to 40 minutes after consumption of an Fentanyl HEXAL unit (range 20-480 minutes).

Distribution

Animal data show that fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat. The plasma protein binding of fentanyl is 80-85 %. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. The mean volume of distribution at steady state (V_ss) is 4 L/kg.

Biotransformation

Fentanyl is metabolised in the liver and in the intestinal mucosa to norfentanyl by CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. More than 90 % of the administered dose of fentanyl is eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Less than 7 % of the dose is excreted unchanged in the urine, and only about 1 % is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important. The total plasma clearance of fentanyl is 0.5 L/hr/kg (range 0.3-0.7 L/hr/kg). The terminal elimination half-life after Fentanyl HEXAL administration is about 7 hours.

Linearity/non-linearity

Dose proportionality across the available range of dosages (200 micrograms to 1,600 micrograms) of Fentanyl HEXAL has been demonstrated.

Paediatric population

In a clinical study, 15 paediatric patients, ranging in age from 5 to 15 years, already receiving maintenance opioid therapy and with breakthrough pain were treated with Fentanyl HEXAL at doses ranging from 200 mcg to 600 mcg. Area under the curve values based on observed concentrations were 2-fold higher in younger children than adolescents (5.25 versus 2.65 ng.hr/mL, respectively) and 4-fold higher in the younger children as compared to adults (5.25 versus 1.20 ng.hr/mL). On a weight-adjusted basis, clearance and volume of distribution values were similar across the age range.

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the oral mucosa and more slowly by the conventional gastrointestinal route. It is subject to first-pass hepatic and intestinal metabolism and the metabolites do not contribute to fentanyl's therapeutic effects.

Fentanyl HEXAL employs a delivery technology which utilises an effervescent reaction which enhances the rate and extent of fentanyl absorbed through the buccal mucosa. Transient pH changes accompanying the effervescent reaction may optimise dissolution (at a lower pH) and membrane permeation (at a higher pH).

Dwell time (defined as the length of time that the tablet takes to fully disintegrate following buccal administration), does not affect early systemic exposure to fentanyl. A comparison study between one 400 mcg Fentanyl HEXAL tablet administered either buccally (i.e., between the cheek and the gum) or sublingually met the criteria of bioequivalence.

The effect of renal or hepatic impairment on the pharmacokinetics of Fentanyl HEXAL has not been studied.

Absorption:

Following oromucosal administration of Fentanyl HEXAL, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of Fentanyl HEXAL is largely the result of an initial rapid absorption from the buccal mucosa, with peak plasma concentrations following venous sampling generally attained within an hour after oromucosal administration. Approximately 50% of the total dose administered is rapidly absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and slowly absorbed from the gastrointestinal tract. About 30% of the amount swallowed (50% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available.

The main pharmacokinetic parameters are shown in the following table.

Pharmacokinetic Parameters* in Adult Subjects Receiving Fentanyl HEXAL

* Based on venous blood samples (plasma). Fentanyl concentrations obtained in serum were higher than in plasma: Serum AUC and Cmax were approximately 20% and 30% higher than plasma AUC and Cmax, respectively. The reason of this difference is unknown.

** Data for T_max presented as median (range).

In pharmacokinetic studies that compared the absolute and relative bioavailability of Fentanyl HEXAL and oral transmucosal fentanyl citrate (OTFC), the rate and extent of fentanyl absorption in Fentanyl HEXAL demonstrated exposure that was between 30% to 50% greater than that for oral transmucosal fentanyl citrate. If switching from another oral fentanyl citrate product, independent dose titration with Fentanyl HEXAL is required as bioavailability between products differs significantly. However, in these patients, a starting dose higher than 100 micrograms may be considered.

Differences in exposure with Fentanyl HEXAL were observed in a clinical study with patients with grade 1 mucositis. C_max and AUC_0-8 were 1% and 25% higher in patients with mucositis compared to those without mucositis, respectively. The differences observed were not clinically significant.

Distribution

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. After buccal administration of Fentanyl HEXAL, fentanyl undergoes initial rapid distribution that represents an equilibration of fentanyl between plasma and the highly perfused tissues (brain, heart and lungs). Subsequently, fentanyl is redistributed between the deep tissue compartment (muscle and fat) and the plasma.

The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

Biotransformation

The metabolic pathways following buccal administration of Fentanyl HEXAL have not been characterised in clinical studies. Fentanyl is metabolised in the liver and in the intestinal mucosa to norfentanyl by CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. More than 90% of the administered dose of fentanyl is eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Following the intravenous administration of fentanyl, less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important.

Following the administration of Fentanyl HEXAL, the terminal elimination phase of fentanyl is the result of the redistribution between plasma and a deep tissue compartment. This phase of elimination is slow, resulting in a median terminal elimination half-life t_1/2 of approximately 22 hours following buccal administration of the effervescent formulation and approximately 18 hours following intravenous administration. The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

Linearity/non-linearity

Dose proportionality from 100 micrograms to 1000 micrograms has been demonstrated.

General introduction

Fentanyl is highly lipophilic and can be absorbed very rapidly through the nasal mucosa and more slowly by the gastrointestinal route. It is subject to first pass hepatic and intestinal metabolism and the metabolites do not contribute to fentanyl's therapeutic effects.

Fentanyl HEXAL utilises the PecSys nasal drug delivery system to modulate the delivery and absorption of fentanyl. The PecSys system allows the product to be sprayed into the front area of the nasal cavity as a fine mist of droplets, which gel on contact with the calcium ions present in the nasal mucosa. Fentanyl diffuses from the gel and is absorbed through the nasal mucosa; this gel-modulated absorption of fentanyl restrains the peak in plasma concentration (C_max) whilst allowing the attainment of an early time to that peak (T_max).

Absorption

In a pharmacokinetic study comparing Fentanyl HEXAL (100, 200, 400 and 800 micrograms) with oral transmucosal fentanyl citrate (OTFC, 200 micrograms), fentanyl was shown to be rapidly absorbed following single dose intranasal administration of Fentanyl HEXAL, with median T_max ranging from 15 to 21 minutes (T_max for OTFC was approximately 90 minutes). The variability of the pharmacokinetics of fentanyl was considerable following treatment with both Fentanyl HEXAL and OTFC. Relative bioavailability of fentanyl from the Fentanyl HEXAL treatment compared to the 200 microgram OTFC was approximately 120 %.

The main pharmacokinetic parameters are shown in the following table.

Pharmacokinetic parameters in adult subjects receiving Fentanyl HEXAL and OTFC

*Data for T_max presented as median (range).

The curves for each dose level are similar in shape with increasing dose levels producing increasing plasma fentanyl levels. Dose-proportionality was demonstrated for C_max and area under the curve (AUC) in the dose range 100 micrograms to 800 micrograms (see Figure 3). If switching to Fentanyl HEXAL from another fentanyl product for BTP, independent dose titration with Fentanyl HEXAL is required as the bioavailability between products differs significantly.

Figure 3: Mean plasma fentanyl concentrations following single doses of Fentanyl HEXAL and OTFC in healthy subjects

A pharmacokinetic study was conducted to evaluate the absorption and tolerability of a single dose of Fentanyl HEXAL in patients with pollen-induced seasonal allergic rhinitis, comparing the un-challenged, acutely challenged (rhinitic) and acutely challenged and then treated with oxymetazoline, states.

There was no clinically significant effect of acute rhinitis on C_max, T_max or overall exposure to fentanyl, comparing the unchallenged with the acutely challenged states. Following treatment of the acute rhinitic state with oxymetazoline, there were reductions in C_max and exposure, and increases in T_max that were statistically, and possibly clinically, significant.

Distribution

Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent volume of distribution. Animal data have shown that, following absorption, fentanyl is rapidly distributed to the brain, heart, lungs, kidneys and spleen followed by a slower redistribution to muscles and fat.

The plasma protein binding of fentanyl is 80 - 85 %. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis.

Biotransformation

The metabolic pathways following nasal administration of Fentanyl HEXAL have not been characterised in clinical studies. Fentanyl is metabolised in the liver to norfentanyl by cytochrome CYP3A4 isoform. Norfentanyl is not pharmacologically active in animal studies. It is more than 90 % eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.

Elimination

Disposition of fentanyl following intranasal administration of Fentanyl HEXAL has not been characterised in a mass balance study. Less than 7 % of an administered dose of fentanyl is excreted unchanged in the urine and only about 1 % is excreted unchanged in the faeces. The metabolites are mainly excreted in the urine, while faecal excretion is less important.

The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.

Linearity/non-linearity

Dose-proportionality was demonstrated for C_max and AUC in the dose range 100 micrograms to 800 micrograms.

The effect of renal or hepatic impairment on the pharmacokinetics of Fentanyl HEXAL has not been studied.

Safety pharmacology and repeated dose toxicity data reveal no special hazard for humans that is not already covered by other sections of this SPC. Animal studies have shown reduced fertility and increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.

Mutagenicity testing in bacteria and in rodents yielded negative results. Like other opioids fentanyl showed mutagenic effects in vitro in mammalian cells. A mutagenic risk with therapeutic use seems unlikely since effects were induced only at very high concentrations.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown.

In vitro Fentanyl HEXAL showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation. Fentanyl HEXAL showed no evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays. In a two-year rat bioassay, Fentanyl HEXAL was not carcinogenic.

Some tests on female rats showed reduced fertility as well as embryo mortality. These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo. There was no evidence of teratogenic effects.

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. There 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 which 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 effects 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.

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. 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. There 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 which 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 effects 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.

Embryo-foetal developmental toxicity studies conducted in rats and rabbits revealed no compound-induced malformations or developmental variations when administered during the period of organogenesis.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at high doses (300 mcg/kg/day, s.c.) and is consistent with the sedative effects of fentanyl in animal studies.

In studies on pre and postnatal development in rats the survival rate of offspring was significantly reduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1 pups were delayed physical development, sensory functions, reflexes and behaviour. These effects could either be indirect effects due to altered maternal care and/or decreased lactation rate or a direct effect of fentanyl on the pups.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not induce any findings indicative of oncogenic potential. Evaluation of brain slides from carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.

Embryo-foetal developmental toxicity studies conducted in rats and rabbits revealed no compound-induced malformations or developmental variations when administered during the period of organogenesis.

In a fertility and early embryonic development study in rats, a male-mediated effect was observed at high doses (300 mcg/kg/day, s.c.) and is considered secondary to the sedative effects of fentanyl in animal studies.

In studies on pre and postnatal development in rats the survival rate of offspring was significantly reduced at doses causing severe maternal toxicity. Further findings at maternally toxic doses in F1 pups were delayed physical development, sensory functions, reflexes and behaviour. These effects could either be indirect effects due to altered maternal care and/or decreased lactation rate or a direct effect of fentanyl on the pups.

Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown.

Waste material should be disposed of safely. Patients/carers should be encouraged to return any unused product to the Pharmacy, where it should be disposed of in accordance with national and local requirements.

CD(2), For IV or IM injection

If only part used, discard the remaining solution.

Instructions for disposal:

Used patches should be folded so that the adhesive side of the patch adheres to itself and then they should be safely discarded. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Contact with the hydrogel can be harmful to humans. If the fentanyl hydrogel contacts the skin during application or removal, the area should be washed with copious amounts of water. Soap, alcohol, or other solvents should not be used to remove the hydrogel because they may enhance the active substances' ability to penetrate the skin.

Disposal

The used Fentanyl HEXAL system contains a dangerous amount of fentanyl within the red hydrogel housing. Gloves must be worn when removing Fentanyl HEXAL from the patient's skin and during disposal. The used system should be handled carefully by the sides and top. Contact with the hydrogel should be avoided.

The design of the system allows separate disposal of the hydrogel housing and the Controller.

To dispose of a used Fentanyl HEXAL system:

1. Hold the Controller in one hand and pull the red tab with the other hand to separate the hydrogel housing from the system.

2. Fold the hydrogel housing in half with the sticky side facing in.

3. Dispose of the folded hydrogel housing in accordance with local requirements for opioid medicinal products.

4. Dispose of remainder of the system, containing electronics, according to hospital procedures for battery waste.

Local arrangements should be in place to ensure that used systems are returned appropriately (e.g., to hospital pharmacies) for disposal of the residual fentanyl in the hydrogel. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Lozenges with residual active substance should at no time be discarded or misplaced. Any used or unused but no longer required product or waste material should be disposed of in accordance with local requirements.

Patients and carers must be advised to dispose of any unopened tablets remaining from a prescription as soon as they are no longer needed.

Any used or unused but no longer required medicinal product or waste material should be disposed of in accordance with local requirements.

Partially used Fentanyl HEXAL bottles may contain enough medicine to be harmful or life-threatening to a child. Even if there is little or no medicine left in the bottle, Fentanyl HEXAL must be disposed of properly, according to the following steps:

o Patients and caregivers must be instructed to properly dispose of all unused, partially used and used Fentanyl HEXAL bottles. The patient should be instructed how to do this correctly.

o If there are any unwanted therapeutic sprays remaining in the bottle, the patient should be instructed to expel these as follows:

2 spray bottle:

o Aim the spray away from themselves (and any other people) and expel remaining spray until the red number “2” appears in the counting window and there are no more full therapeutic sprays obtainable from the bottle.

o After the counter has advanced to “2”, the patient should continue to push down on the finger grips (there will be some increased resistance) a total of four times in order to expel any residual medicine from the bottle.

o After the 2 therapeutic sprays have been emitted, the patient will not hear a click and the counter will not advance beyond “2”; further sprays emitted will not be full sprays and should not be used therapeutically.

8 spray bottle:

o Aim the spray away from themselves (and any other people) and expel remaining spray until the red number “8” appears in the counting window and there are no more full therapeutic sprays obtainable from the bottle.

o After the counter has advanced to “8”, the patient should continue to push down on the finger grips (there will be some increased resistance) a total of four times in order to expel any residual medicine from the bottle.

o After the 8 therapeutic sprays have been emitted, the patient will not hear a click and the counter will not advance beyond “8”; further sprays emitted will not be full sprays and should not be used therapeutically.

As soon as Fentanyl HEXAL is no longer needed, patients and members of their household must be advised to systematically dispose of any bottles remaining from a prescription as soon as possible by returning them to their child-resistant container and discarding them, according to local requirements or by returning them to the pharmacy.