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Takeda Products Ireland Ltd

First Floor, 3013 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Telephone: +353 1 642 0021
Fax: +353 1 642 0020
Medical Information Direct Line: 1800 937970
Medical Information e-mail: DSO-UK@takeda.com
Medical Information Facsimile: +44 (0)1628 526 617
Summary of Product Characteristics last updated on medicines.ie: 14/07/2017
SPC Matrifen Transdermal patch

When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 14/07/2017 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text
  • Change to section 4.3 - Contraindications
Date of revision of text on the SPC:   21-Jun-2017
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



The Summary of Product Characteristics (SmPC) for Matrifen has been updated to harmonise the prescribing information in the EU for all fentanyl containing patch products.

The following information has been added to the sections listed below:

Updated text is shown in red.

Details of change

4.1 Therapeutic indications

Adults:

Matrifen 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. 

 

Adults:

Severe chronic pain, which can be adequately managed only with opioid analgesics.

 

Children:

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

 

 

4.2 Posology and method of administration

Posology

 

Matrifen 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.

Fentanyl transdermal patches release the active substance over 72 hours. The fentanyl release rate is 12, 25, 50, 75 and 100 microgram/hour and the corresponding active surface area is 4.2, 8.4, 16.8, 25.2 and 33.6 cm2.

The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.

 

Initial dosage selection

The appropriate initiating dose of Matrifen should be based on the patient’s current opioid use. It is recommended that Matrifen 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.

 

Choice of initial dosage

The dosage level of fentanyl is based upon the previous use of opioids and takes into account the possible development of tolerance, concomitant medicinal treatment, the patient's general state of health and the degree of severity of the disorder.

 

Opioid-naive patients

 

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

In the circumstance in which commencing with oral opioids is not considered possible and Matrifen 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 Matrifen is used in initiating therapy in opioid-naïve patients (see sections 4.4 and 4.9).

 

The initial dosage should not exceed 12 micrograms/hour when the opioid response pattern for the pain condition is not fully known.

 

Clinical experience with fentanyl transdermal patch is limited in opioid-naïve patients. In the circumstances in which therapy with fentanyl transdermal patch is considered appropriate in opioid-naïve patients, it is recommended that these patients be titrated with low doses of immediate release opioids (e.g., morphine, hydromorphone, oxycodone, tramadol, and codeine) to attain equianalgesic dosage relative to fentanyl transdermal patch. Patients can then be converted to fentanyl transdermal patch. The dose may subsequently be titrated upwards or downwards, if required, in increments of 12 or 25 mcg/hr to achieve the lowest appropriate dose of fentanyl transdermal patch depending on the response and supplementary analgesic requirements (see also section 4.4 Special warnings and precautions for use: Opioid naïve and not opioid-tolerant states).

 

Equianalgesic potency conversion

 

In patients currently taking opioid analgesics, the starting dose of Matrifen should be based on the daily dose of the prior opioid. To calculate the appropriate starting dose of Matrifen, 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 Matrifen 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).

 

1. Calculate the previous 24-hour analgesic requirement.

 

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

 

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

 

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

 

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

 

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

 

Table 1: Equianalgesic potency conversion

 

Name of medicinal product

Equianalgesic dosage (mg)

 

i.m.*

Oral

 

 

 

Morphine

10

30 - 40 (assuming repeated administration)**

 

 

60 (assuming a single dose or occasional doses)

Hydromorphone

1.5

7.5

Methadone

10

20

Oxycodone

10-15

20-30

Levorphanol

2

4

Oxymorphine

1

10 (rectal)

Diamorphine

5

60

Pethidine

75

-

Codeine

 

200

Buprenorphine

0.4

0.8 (sublingual)

Ketobemidone

10

30

 

 

 

 

* Based on studies conducted with single doses, in which the i.m. dosage of each above-mentioned agent was compared with morphine in order to achieve an equivalent efficacy. Oral dosages are the recommended dosages when changing from parenteral to oral administration.

** The efficacy ratio of 3:1 for morphine i.m./oral dosages is based upon a study conducted in patients suffering from chronic pain.

 

Table 1: Conversion Table - Multiplication Factors for Converting the Daily Dose of Prior Opioids to the Equianalgesic 24-hour Oral Morphine Dose

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

 

Prior Opioid

Route of Administration

Multiplication Factor

Morphine

oral

1a

parenteral

3

Buprenorphine

sublingual

75

parenteral

100

Codeine

oral

0.15

parenteral

0.23b

Diamorphine

oral

0.5

parenteral

6b

Fentanyl

oral

-

parenteral

300

Hydromorphone

oral

4

parenteral

20b

Ketobemidone

oral

1

parenteral

3

Levorphanol

oral

7.5

parenteral

15b

Methadone

oral

1.5

parenteral

3b

Oxycodone

oral

1.5

parenteral

3

Oxymorphone

rectal

3

parenteral

30b

Pethidine

oral

-

parenteral

0.4b

Tapentadol

oral

0.4

parenteral

-

Tramadol

oral

0.25

parenteral

0.3

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

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

 

Table 2: Recommended initial dose of Matrifen based upon daily oral morphine dose (for patients stabilised on oral morphine or immediate release opioid for several weeks and who need opioid rotation)

 

Oral morphine dose per 24-hours (mg/day)

Dose of Matrifen transdermal patch micrograms/hour

<44

12

45-134

25

135-224

50

225-314

75

315-404

100

405-494

125

495-584

150

585-674

175

675-764

200

765-854

225

855-944

250

945-1034

275

1035-1124

300

 

 

 

Conversion schemes are based on clinical trials. Schemes based on other trials have been found useful in clinical practice and may be used.

 

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

 

Oral 24-hour morphine

(mg/day)

Matrifen

Dosage

(mcg/h)

<90

12

90-134

25

135-224

50

225-314

75

315-404

100

405-494

125

495-584

150

585-674

175

675-764

200

765-854

225

855-944

250

945-1034

275

1035-1124

300

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

 

 

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

 

Oral 24-hour morphine

(mg/day)

Matrifen

Dosage

(mcg/h)

< 44

12

45-89

25

90-149

50

150-209

75

210-269

100

270-329

125

330-389

150

390-449

175

450-509

200

510-569

225

570-629

250

630-689

275

690-749

300

 

Initial evaluation of the maximum analgesic effect of Matrifen 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 Matrifen is attained.

 

Previous analgesic therapy should be phased out gradually from the time of the first patch application until analgesic efficacy with Matrifen is attained. For both strong opioid-naïve and opioid tolerant patients, the initial evaluation of the analgesic effect of Matrifen should not be made until the patch has been worn for 24 hours due to the gradual increase in serum fentanyl concentrations up to this time.

 

Dose titration and maintenance therapy

The Matrifen 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 ≈ Matrifen 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 Matrifen 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 Matrifen dose exceeds 300 mcg/h.

 

If analgesia is insufficient during the first application only, the Matrifen 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 (see section 5.2) and the patient should be monitored closely.

 

The patch should be replaced every 72 hours. The dose should be titrated individually until a balance between analgesic efficacy and tolerability is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of fentanyl after 48 hours may be necessary. The dose 12 micrograms/hour is appropriate for dose titration in the lower dosage area. If analgesia is insufficient at the end of the initial application period, the dose may be increased after 3 days, until the desired effect is obtained for each patient. Additional dose adjustment should normally be performed in 12 micrograms/hour or 25 micrograms/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account. More than one patch may be used for dose adjustments and for doses greater than 100 micrograms/hour. Patients may require periodic supplemental doses of a short-acting analgesic for breakthrough pain. Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the Matrifen dose exceeds 300 micrograms/hour.

 

Opioid withdrawal symptoms (see section 4.8, Undesirable effects) have been reported when changing from long-term treatment with Morphine to transdermal fentanyl despite adequate analgesic efficacy. In case of withdrawal symptoms it is recommended to treat those with short-acting Morphine in low doses.

 

Discontinuation of Matrifen

If discontinuation of Matrifen 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 Matrifen is removed. It may take 20 hours or more for the fentanyl serum concentrations to decrease 50%. In general, the discontinuation of opioid analgesia should be gradual in order to prevent withdrawal symptoms (see section 4.8).

 

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 Matrifen and not from Matrifen to other therapies to avoid overestimating the new analgesic dose and potentially causing overdose.

 

If discontinuation of the patch is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl levels fall gradually after the patch is removed; it takes at least 17 hours for the fentanyl serum concentration to decrease by 50% (see section 5.2). As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (nausea, vomiting, diarrhea, anxiety and muscular tremor).

 

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

 

Special populations

 

Elderly patients

Elderly patients should be observed carefully and the dose should be individualised based upon the status of the patient (see sections 4.4 and 5.2).

 

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

 

Renal and hepatic impairment

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

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

 

Use in older people

Elderly or cachectic patients should be observed carefully and the dose reduced if necessary (see section 4.4).

 

Use in patients with hepatic or renal impairment

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

 

Use in febrile patients

Dose adjustment may be necessary in patients during episodes of fever (see section 4.4).

 

Use in

 

Paediatric population

 

Children aged 16 years and above

Follow adult dosage.

 

Children aged 2 to 16 years old

Matrifen 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 Matrifen, refer to Equianalgesic potency conversion (Table 1) and Recommended Matrifen dosage based upon daily oral morphine dose (Table 4).

 

Matrifen should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalent per day. To convert paediatric patients from oral or parenteral opioids to Matrifen, refer to Equianalgesic efficacy of medicinal products (Table 1), and Recommended initial Matrifen dose based upon daily oral morphine dose (Table 4).

 

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

Oral 24-hour morphine

(mg/day)

Matrifen

Dosage

(mcg/h)

30-44

12

45-134

25

1 Conversion to Matrifen 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 Matrifen.

 

In two paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 44 mg oral morphine per day or its equivalent opioid dose was replaced by one transdermal fentanyl 12 mcg/h patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to fentanyl transdermal patches. The conversion schedule should not be used to convert from transdermal fentanyl into other opioids, as overdosing could then occur.

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

Matrifen 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 Matrifen 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 Matrifen 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.

 

For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 44 mg oral morphine per day or its equivalent opioid dose was replaced by one fentanyl 12 microgram/hour patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to fentanyl patches. The conversion schedule could not be used to convert from fentanyl into other opioids, as overdose could then occur.

 

The analgesic effect of the first dose of Matrifen patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Matrifen, the patients should be given the previous regular dose of analgesics. In the next 12 hours, these analgesics should be provided based on clinical need.

 

Since peak fentanyl levels occur after 12 to 24 hours of treatment, monitoring of the patient for adverse events, which may include hypoventilation, is recommended for at least 48 hours after initiation of Matrifen therapy or up-titration of the dose (see also section 4.4 Special warnings and precautions for use).

 

Dose titration and maintenance.

If the analgesic effect of Matrifen 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 micrograms/hour steps.

 

Method of administration

Matrifen is for transdermal use.

 

Matrifen 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 Matrifen 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.

 

Matrifen 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.

 

Matrifen 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 transdermal patch should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arm. In young children the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch. Hair at the application site (hairless area is preferred) should be clipped (not shaved) prior to system application. If the site requires to be cleansed prior to application of the patch, this should be done with water. Soaps, oils, lotions, alcohol or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before application of the patch.

 

Patches should be inspected prior to use. The transdermal patch should not be divided or cut (see section 4.4) Patches that are cut, divided, or damaged in any way should not be used.

 

Since the transdermal patch is protected outwardly by a waterproof covering foil, it may also be worn when taking a short shower.

 

The Matrifen patch should be removed from the protective pouch by first folding the notch (located close to the tip of the arrow on the pouch label) and then carefully tearing the pouch material. If scissors are used to open the pouch, this should be done close to the sealed edge so as not to damage the patch inside.

 

Fentanyl transdermal patch is to be attached as soon as the pack has been opened and avoid touching the adhesive side of the patch.

 

Following removal of the protective layer, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges. An additional fixing of the transdermal patch may be necessary. . Then wash hands with clean water.

 

Fentanyl transdermal patch should be worn continuously for 72 hours after which the transdermal patch is replaced. A new transdermal patch should always be applied to a different site from the previous one. The same application site may be re-used only after an interval of at least 7 days.

 

 

For disposal instructions see section 6.6.

4.3 Contraindications

 

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

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

-          Severe respiratory depression.

 

Matrifen is contraindicated in patients with known hypersensitivity to fentanyl or to any of the excipients listed in section 6.1.

 

Acute or postoperative pain, since dose titration is not possible during short-term use and because of the possibility of serious or life‑threatening hypoventilation.

 

4.4 Special warnings and precautions for use

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

 

Patients who have experienced serious adverse events should be monitored for up to 24 hours after fentanyl transdermal patch removal since serum fentanyl concentrations decline gradually and are reduced by about 50 % 17 (range 13-22) hours later.

 

Fentanyl transdermal patches should be kept out of sight and reach of children before and after use.

 

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

 

Opioid-naïve and not opioid-tolerant states

Use of Matrifen 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 Matrifen 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 Matrifen is used in patients who have demonstrated opioid tolerance (see section 4.2).

 

Respiratory depression

Some patients may experience significant respiratory depression with Matrifen; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the Matrifen patch. The incidence of respiratory depression increases as the Matrifen dose is increased (see section 4.9). Central nervous system depressants may increase the respiratory depression (see section 4.5).

 

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

 

Serotonin Syndrome

Caution is advised when fentanyl transdermal patches is coadministered with drugs that affect the serotonergic neurotransmitter systems.

 

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

 

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

 

If serotonin syndrome is suspected, rapid discontinuation of fentanyl transdermal patches should be considered.

 

Chronic pulmonary disease

Matrifen 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 Matrifen 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.

 

Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids such as fentanyl. Iatrogenic addiction following opioid administration is rare. Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require monitoring for signs of misuse, abuse, or addiction. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Matrifen may result in overdose and/or death.

 

Central Nervous System conditions including increased intracranial pressure

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

 

Renal impairment

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

 

Fever/external heat application

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

 

 

Interactions with other medicinal products

CYP3A4 inhibitors

The concomitant use of Matrifen 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 Matrifen 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 Matrifen 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 Matrifen patch. A patient who is treated with Matrifen should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor. If concomitant use of Matrifen 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 Matrifen dosage must be reduced or interrupted as deemed necessary (see section 4.5).

 

Accidental exposure by patch transfer

Accidental transfer of a fentanyl patch to the skin of a non-patch wearer (particularly a child), while sharing a bed or being in close physical contact with a patch wearer, may result in an opioid overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs, the transferred patch must be removed immediately from the skin of the non-patch wearer (see section 4.9).

 

Use in elderly patients

Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the active substance than younger patients. If elderly patients receive Matrifen, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).

 

Gastrointestinal tract

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

 

Patients with myasthenia gravis

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

 

Concomitant use of mixed opioid agonists/antagonists

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

 

Paediatric population

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

 

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

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

 

Increased intracranial pressure

Matrifen 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 should be used with caution in patients with brain tumors.

 

Cardiac disease

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

 

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

 

Hepatic impairment

Because fentanyl is metabolised to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive transdermal fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose of fentanyl reduced if necessary (see Section 5.2, Pharmacokinetic properties).

 

Renal impairment

Less than 10% of fentanyl is excreted unchanged by the kidney and, unlike morphine, there are no known active metabolites eliminated by the kidney. If patients with renal impairment receive transdermal fentanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 5.2, Pharmacokinetic properties).

 

Fever/external heat application

A pharmacokinetic model suggests that serum fentanyl concentrations may increase by about one-third if the skin temperature increases to 40° C.

Therefore, patients with fever should be monitored for opioid side effects and the fentanyl dose should be adjusted if necessary. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. A clinical pharmacology trial conducted in healthy adult subjects has shown that the application of heat over a fentanyl transdermal system increased mean fentanyl AUC values by 120% and mean Cmax values by 61%.

 

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

 

Interactions with other Medicinal Products

Interactions with CYP3A4 Inhibitors:

The concomitant use of transdermal fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, erythromycin, nelfinavir, nefazodone, verapamil, diltiazem, and amiodarone) may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. In this situation special patient care and observation are appropriate. Therefore, the concomitant use of transdermal fentanyl and CYP3A4 inhibitors is not recommended unless the patient is closely monitored. Patients, especially those who are receiving transdermal fentanyl and CYP3A4 inhibitors, should be monitored for signs of respiratory depression and dosage adjustments should be made if warranted.

 

Older Patients

Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the drug than younger patients. If elderly patients receive transdermal fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 5.2, Pharmacokinetic properties).

 

Gastrointestinal Tract

 

Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Patients should be advised 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 patch should be stopped.

 

Accidental Exposure by Patch Transfer

Accidental transfer of a fentanyl patch to the skin of a non-patch wearer (particularly a child), while sharing a bed or being in close physical contact with a patch wearer, may result in an opioid overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs, the transferred patch must be removed immediately from the skin of the non-patch wearer. (see section 4.9 Overdose)

 

Use in paediatrics

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

Fentanyl transdermal patch was not studied in children under 2 years of age. Matrifen should be administered only to opioid-tolerant children age 2 years or older (see section 4.2 Posology and method of administration). Matrifen should not be used in children under 2 years of age.

 

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

 

Lactation

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

 

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 agonists/antagonists

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

 

 

Continued…

4.5 Interaction with other medicinal products and other forms of interaction

 

 

Pharmacodynamic-related interactions

 

Centrally-acting medicinal products and alcohol

The concomitant use of other central nervous system depressants, (including opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquilizers, sedating antihistamines, and alcoholic beverages) and skeletal muscle relaxants, may produce additive depressant effects; hypoventilation, hypotension, profound sedation, coma or death may occur. Therefore, the use of any of these medicinal products concomitantly with Matrifen requires special patient care and observation.

 

Monoamine Oxidase Inhibitors (MAOI)

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

 

Serotonergic medicinal products

Co-administration of fentanyl with a serotonergic medicinal products, such a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor  (MAOI), may increase the risk of serotonin syndrome, a potentially life threatening condition.

 

Concomitant use of mixed opioid agonists/antagonists

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependent patients (see also Section 4.4).

 

Pharmacokinetic-related interactions

 

CYP3A4 Inhibitors

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

 

The concomitant use of Matrifen with cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. The extent of interaction with strong CYP3A4 inhibitors is expected to be greater than with weak or moderate CYP3A4 inhibitors.

 

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

 

CYP3A4 Inducers

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

 

Paediatric population

Interaction studies have only been performed in adults.

 

 

The concomitant use of other central nervous system depressants, including opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce additive depressant effects; hypoventilation, hypotension, and profound sedation, coma or death may occur. Therefore, the use of any of these drugs concomitantly with transdermal fentanyl requires special patient care and observation.

 

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

 

The concomitant use of transdermal fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir, ketoconazol, itraconazol, fluconazole, voriconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, verapamil, diltiazem, and amiodarone) may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects,and may cause serious respiratory depression. In this situation, special patient care and observation are appropriate. The concomitant use of CYP3A4 inhibitors and transdermal fentanyl is not recommended, unless the patient is closely monitored (See also Special warnings and precautions for use, Section 4.4).

 

The concomitant use with CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin) could result in a decrease in fentanyl plasma concentrations and a decreased therapeutic effect. This may require a dose adjustment of transdermal fentanyl. After stopping the treatment of a CYP3A4 inducer, the effects of the inducer decline gradually and may result in a fentanyl plasma increase concentration which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. In this situation, careful monitoring and dose adjustment should be made if warranted.

 

Monoamine Oxidase Inhibitors (MAOI):

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

 

Serotonergic Drugs

 

Coadministration of transdermal fentanyl with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition.

 

Concomitant use of mixed agonists/antagonists

The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependent patients (see also Section 4.4).

 

Continued…

4.6 Fertility, pregnancy and lactation

 

Pregnancy

 

There are no adequate data from the use of Matrifen in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown, although fentanyl as an IV anaesthetic has been found to cross the placenta in human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of Matrifen during pregnancy. Matrifen should not be used during pregnancy unless clearly necessary.

 

Use of Matrifen during childbirth is not recommended because it should not be used in the management of acute or postoperative pain (see section 4.3). Moreover, because fentanyl passes through the placenta, the use of Matrifen during childbirth might result in respiratory depression in the newborn infant.

 

There are no adequate data from the use of transdermal fentanyl in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3 Preclinical safety data). The potential risk for humans is unknown, although fentanyl as an IV anesthetic has been found to cross the placenta in early human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of transdermal fentanyl during pregnancy. Transdermal fentanyl should not be used during pregnancy unless clearly necessary.

 

Use of transdermal fentanyl during childbirth is not recommended because it should not be used in the management of acute or postoperative pain (see Section 4.4, Special warnings and precautions for use). Moreover, because fentanyl passes through the placenta, the use of transdermal fentanyl during childbirth might result in respiratory depression in the newborn infant.

 

Breastfeeding

 

Fentanyl is excreted into breast milk and may cause sedation/respiratory depression in a breastfed infant. Breastfeeding should therefore be discontinued during treatment with Matrifen and for at least 72 hours after removal of the patch.

 

Fertility

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

 

4.7 Effects on ability to drive and use machines

 

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

 

4.8 Undesirable effects

 

The safety of transdermal fentanyl was evaluated in 1565 adult and 289 paediatric subjects who participated in 11 clinical studies (1 double-blind, placebo-controlled; 7 open-label, active-controlled; 3 open-label, uncontrolled) used for the management of chronic malignant or non-malignant pain. These subjects received at least one dose of transdermal fentanyl 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 transdermal fentanyl from these clinical studies, including the above-mentioned adverse reactions, and from post-marketing experiences are listed below in Table 5.

 

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

 

The safety of transdermal fentanyl was evaluated in 1854 subjects who participated in 11 clinical trials (double-blind transdermal fentanyl [placebo or active control] and/or open label transdermal fentanyl [no control or active control]) used for the management of chronic malignant or non-malignant pain. These subjects took at least 1 dose of transdermal fentanyl and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported adverse drug reactions (ADRs) were (with % incidence): nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).

 

The ADRs reported with the use of transdermal fentanyl from these clinical trials, including the above-mentioned ADRs, and from post-marketing experiences are listed below.

 

The displayed frequency categories use the following convention: very common (³1/10); common (³1/100 to <1/10); uncommon (³1/1,000 to <1/100); rare (³1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

 

Table 5: Adverse Drug Reactions in Adult and Paediatric Subjects

 

Table 5:Adverse Drug Reactions in Adult and Paediatric Subjects

 

System /Organ Class

 

Frequency Category

Very 

common

Common

Uncommon

Rare

Not Known

Immune System Disorders

 

Hypersensitivity

 

 

Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction

Metabolism and Nutrition Disorders

 

Anorexia

 

 

 

Psychiatric Disorders

 

Insomnia, Depression, Anxiety, Confusional 

state, Hallucination

Agitation, Disorientation, Euphoric mood

 

 

Nervous System Disorders

Somnolence, Dizziness, Headache

Tremor, Paraesthesia

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

 

 

Eye Disorders

 

 

Vision blurred

Miosis

 

Ear and Labyrinth Disorders

 

Vertigo

 

 

 

Cardiac Disorders

 

Palpitations, Tachycardia

Bradycardia, Cyanosis

 

 

Vascular Disorders

 

Hypertension

Hypotension

 

 

Respiratory, Thoracic and Mediastinal Disorders

 

Dyspnoea

Respiratory depression, Respiratory distress

Apnoea,
Hypoventilation

Bradypnoea,

Gastrointestinal Disorders

Nausea, Vomiting, Constipation

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

Ileus

Subileus

 

 

 

 

Skin and Subcutaneous Tissue Disorders

 

Hyperhidrosis, Pruritus, Rash, Erythema

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

 

 

Musculoskeletal and Connective Tissue Disorders

 

Muscle spasms

Muscle twitching

 

 

Renal and Urinary Disorders

 

Urinary retention

 

 

 

Reproductive System and Breast Disorders

 

 

Erectile dysfunction, Sexual dysfunction

 

 

 

General Disorders and Administration Site Conditions

 

Fatigue, Oedema peripheral, Asthenia, Malaise, Feeling cold

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

Application site dermatitis, Application site eczema

 

* 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 transdermal patch 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 transdermal patch and provided safety data (see section 5.1).

 

The safety profile in children and adolescents treated with fentanyl transdermal patch 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 transdermal patch 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 (see section 4.4).

 

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to fentanyl transdermal patch or if therapy is stopped suddenly (see section 4.2).

 

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

 

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

 

As with other opioid analgesics, tolerance, physical dependence and psychological dependence can develop on repeated use of fentanyl (see Section 4.4, Special warnings and special precautions for use).

 

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesics to fentanyl transdermal patch or if therapy is stopped suddenly (see Section 4.2, Posology and method of administration). There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used transdermal fentanyl during pregnancy (see Section 4.6, Fertility, pregnancy and lactation).

 

Paediatric Subjects

The adverse event profile in children and adolescents treated with fentanyl transdermal patch 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 transdermal patch use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, vomiting and nausea.

 

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

 

Based on pooled safety data from these 3 clinical trials in paediatric subjects, the most commonly reported (ie ≥10% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): vomiting (33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%). Table 6 displays all ADRs reported in fentanyl transdermal patch-treated paediatric subjects in the aforementioned clinical trials.

 

The ADRs for the paediatric population presented in Table 6 were assigned to frequency categories using the same conventions as used for Table 5.

 

Table 6: Adverse Drug Reactions in Paediatric Subjects in clinical trials

 

 

 

 

System Organ Class

Adverse Drug Reactions

Frequency Category

Very Common (≥1/10)

Common

Uncommon

Immune System Disorders

 

Hypersensitivity

 

Metabolism and Nutrition Disorders

 

Anorexia

 

Psychiatric Disorders

 

Insomnia Somnolence,

Anxiety, Depression,

Hallucination

Confusional state

Nervous System Disorders

Headache

Dizziness, Tremor, Hypoaesthesia,

Paraesthesia

Eye Disorders

 

 

Miosis

Ear and Labyrinth Disorders

 

 

Vertigo

Cardiac Disorders

 

 

Cyanosis

 

 

 

 

Respiratory, Thoracic and Mediastinal Disorders

 

Respiratory depression,

 

Gastrointestinal Disorders

Nausea, Vomiting, Constipation, Diarrhoea,

Abdominal pain, Abdominal pain upper, Dry mouth

 

Skin and Subcutaneous Tissue Disorders

Pruritus,

Rash, Hyperhidrosis, Erythema

Contact dermatitis, Skin disorder, Allergic dermatitis, Eczema,

Musculoskeletal and Connective Tissue Disorders

 

Muscle spasms

 

Renal and Urinary Disorders

 

Urinary retention

 

General Disorders and

Administration Site

Conditions

 

Peripheral oedema Fatigue,

Application site reaction,

Asthenia

Drug withdrawal syndrome,

Influenza-like illness

 

Continued…

4.9 Overdose

Symptoms and signs

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

 

Treatment

For management of respiratory depression, immediate countermeasures include removing the Matrifen 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, hypovolaemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.

 

 

5.1 Pharmacodynamic properties

 

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.

 

Matrifen is a transdermal patch that provides continuous delivery of fentanyl. Fentanyl is an opioid analgesic with affinity mainly to the µ-receptor. The predominant pharmacological effects are pain relief and sedation. Patients not previously treated with opioids will have pain relief at a fentanyl concentration between 0.3 and 1.5 ng/ml. In this group of patients the frequency of adverse effects will increase at serum concentrations above 2 ng/ml. Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. Development of tolerance varies considerably between individual subjects.

 

Paediatric population

The safety of transdermal fentanyl 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 transdermal fentanyl 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 (see section 4.8).

 

The safety of transdermal fentanyl was evaluated in three open-label trials in 289 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged to 2 to 6 years. In these studies, 30 mg to 45 mg oral morphine per day was replaced by one transdermal fentanyl 12 microgram/h patch. Starting dose of 25 microgram/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg per dose of oral morphine

 

 

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5.2 Pharmacokinetic properties

The fentanyl transdermal patch provides systemic delivery over the 72 hour administration period.

 

Absorption

After the first patch application serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours and remaining relatively constant for the remainder of the 72-hour application period. By the second 72-hour application, a steady- state serum concentration is reached and is maintained during subsequent applications of the patch of the same size. The absorption of fentanyl may differ somewhat between different application sites. A somewhat lower (approximately 25%) fentanyl absorption has been observed in studies with healthy volunteers after the patch has been applied on the chest compared with the upper arm and the back.

 

Absorption

The fentanyl transdermal patch provides continuous systemic delivery of fentanyl during the 72-hour application period. Following patch 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 patch 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 Cmax 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 (see section 4.4). An increase in skin temperature through the application of a heating pad on low setting over the Matrifen 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