Matrifen Transdermal patch

Section

Changes

4.2 Posology and method of administration

Added 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.

4.8 Undesirable effects

Added:

Endocrine disorders

Androgen deficiency (frequency not known)

Psychiatric Disorders

Delirium (frequency not known)

10. DATE OF REVISION OF THE TEXT

14th October 2019

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).

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.

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.

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

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.

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.

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

Continued…

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 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 (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

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.

The plasma protein binding for fentanyl is 84 %.

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.

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

Elimination

After the fentanyl patch is removed, serum fentanyl concentrations decline gradually falling approximately 50% in 13-22 hours in adults or 22-25 hours in children. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an intravenous infusion. Around 75% of fentanyl is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of the dose is recovered in the faeces, primarily as metabolites.

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 transdermal patch size. The pharmacokinetics of transdermal fentanyl do not change with repeated application.

Pharmacokinetics in special groups

Impaired hepatic or renal function could cause increased serum concentrations. Elderly, cachectic or generally impaired patients may have a lower fentanyl clearance, which could cause a longer terminal half life for the compound (see section 4.2 and 4.4).

Paediatric population

5.3 Preclinical safety data

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

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. As well as other opioids fentanyl showed mutagenic effects in vitro in mammalian cells. A mutagenic risk in therapeutic condition seems unlikely since effects were induced only in very high concentrations.

6.5 Nature and contents of container

Each patch is packed in a heat-sealed pouch sachet made of paper, aluminium and polyacrylonitrile (PAN).

6.6 Special precautions for disposal and other handling

Please refer to section 4.2 for Instructions on how to apply the patch. There are no safety and pharmacokinetic data available for other application sites.

Instructions for disposal:

10 DATE OF REVISION OF THE TEXT

2015-04-17

2017-06-21

Change to section

Details of change

3. Pharmaceutical form

Changed:

The pPatches are equipped marked with a coloured imprint with stating the trade name and strength:

4.2. Posology and method of administration

Added:

Posology (Heading added)

Fentanyl transdermal patches release the active substance over 72 hours.

The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration. (taken from Method of Administration)

Added:

4.3. Contraindications

Added:

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.

Severe respiratory depression.

Severe impairment of the central nervous system.

4.4.  Special warnings and precautions for use

Deleted:

Transdermal fentanyl should not be used in the management of acute or postoperative pain since there is no opportunity for dose titration during short-term use and because serious or life threatening hypoventilation could result.

It is not possible to ensure the interchangeability of different makes of fentanyl transdermal patches in individual patients. Therefore, it should be emphasised that patients should not be changed from one make of fentanyl transdermal patches to another without specific counselling on the change from their healthcare professionals.

Added:

4.5. Interaction with other medicinal products and other forms of interaction

Added:

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.

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.

4.8. Undesirable Effects

Added:

Title to Table: Table 5: Adverse Drug Reactions in Adult and Paediatric Subjects.

Within Table 5, the following amends have been made:

Insomnia moved to Common Psychiatric Disorders

Somnolence  moved to Nervous System Disorders

Depressed level of consciousness, Loss of consciousness added to Nervous System Disorders as Uncommon

Pyrexia added to General Disorders and Administration Site Conditions as Uncommon

Added:

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.

New table added:

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

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

10. DATE OF REVISION OF THE TEXT

Changed to:

22^nd April 2015