Mezolar Matrix 37.5 Microgram/Hour Transdermal Patch
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Mezolar Matrix 37.5 microgram/hour transdermal patch
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each patch releases 37.5 micrograms fentanyl per hour. Each patch of 15.75 cm2 contains 6.3 mg fentanyl.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Transdermal patch
Transparent rounded oblong transdermal patch with imprint on the backing film: “fentanyl 37.5 pg/h”
The patch consists of a release liner (to be removed prior to application of the patch) and two functional layers: one self-adhesive matrix layer containing fentanyl and a backing film impermeable to water.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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
Fentanyl transdermal patches release fentanyl over 72 hours.
The dosing is individual and based on the patient's opioid history and takes into account:
- the possible development of tolerance,
- the current general condition, the medical status of the patient, and
- the degree of severity of the disorder.
The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.
Adults:
Patients receiving opioid treatment for the first time
In patients who have not previously received strong opioids, the initial dosage should not exceed 12.5-25 microgram/hour.
In older or weak patients, it is not recommended to initiate an opioid treatment with fentanyl transdermal patches, due to their known susceptibility to opioid treatments. In these cases, it would be preferable to initiate a treatment with low doses of immediate release morphine and to prescribe fentanyl transdermal patches after determination of the optimal dosage.
Switching from other opioids
When changing over from oral or parenteral opioids to fentanyl treatment, the initial dosage should be calculated as follows:
1. The quantity of analgesics required over the last 24 hours should be determined.
2. The obtained sum should be converted to the corresponding oral morphine dosage using Table 1.
3. The corresponding fentanyl dosage should be determined as follows:
a) using Table 2 for patients who have a need for opioid rotation (conversion ratio of oral morphine to transdermal fentanyl equal to 150:1)
b) using Table 3 for patients on stable and well tolerated opioid therapy (conversion ratio of oral morphine to transdermal fentanyl equal to 100:1)
Table 1: Equianalgesic potency conversion
All dosages given in the table are equivalent in analgesic effect to 10 mg parenteral
|
morphine. |
Active substance |
Equianalgesic doses (mg) |
|
i.m. |
Oral | |
|
Morphine |
10 |
30-40 |
|
Hydromorphone |
1.5 |
7.5 |
|
Oxycodone |
10-15 |
20-30 |
|
Methadone |
10 |
20 |
|
Levorphanol |
2 |
4 |
|
Oxymorphine |
1 |
10 (rectal) |
|
Diamorphine |
5 |
60 |
|
Pethidine |
75 |
- |
|
Codeine |
- |
200 |
|
Buprenorphine |
0.4 |
0.8 (sublingual) |
|
Ketobemidone |
10 |
20-30 |
Table 2: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose
(for patients who have a needfor opioid rotation)
Oral
Transdermal fentanyl release (micrograms/h)
12.5
morphine dose (mg/24 h)
For paediatric patients 30-44
For adults
* Conversion to fentanyl transdermal patch doses greater than 25 microgram/hour is the same for adult and paediatric patients.
Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose
(for patients on stable and well tolerated opioid therapy)
Oral
morphine dose (mg/24 h)
<60
60-89
90-119
120-149
150-209
210-269
270-329
330-389
390-449
450-509
510-569
570-629
630-689
690-749
Transdermal fentanyl release (micrograms/h)
12.5 25
37.5 50 75 100 125 150 175 200 225 250 275 300
By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/h can be achieved.
The initial evaluation of the maximum analgesic effect of Mezolar Matrix transdermal patch should not be made before the patch has been worn for 24 hours. This is due to the gradual increase in serum fentanyl concentrations during the first 24 hours after application of the patch.
In the first 12 hours after changing to Mezolar Matrix transdermal patch the patient continues to receive the previous analgesic at the previous dose; over the next 12 hours this analgesic is administered according to need.
Dose titration and maintenance therapy
The Mezolar Matrix transdermal patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of Mezolar Matrix transdermal patch after 48 hours may be necessary. The dose 12.5 microgram/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 12.5 microgram/hour or 25 microgram/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account. Patients may require periodic supplemental doses of a short-acting analgesic for breakthrough pain (e. g. morphine). Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the transdermal fentanyl dose exceeds 300 microgram/hour.
Withdrawal symptoms 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.
Changing or ending therapy
If discontinuation of Mezolar Matrix transdermal 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 Mezolar Matrix transdermal 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 (such as nausea, vomiting, diarrhea, anxiety and muscular tremor).
Tables 2 and 3 should not be used to switch form transdermal fentanyl to a morphine treatment.
Older patients
Older patients should be observed carefully for signs of toxicity and the dose reduced if necessary (see sections 4.4 and 5.2).
Paediatric population
Mezolar Matrix transdermal patch should not be used in children under 2 years of age.
Children aged 16 years and above:
Follow adult dosage
Children aged 2 to 16 years:
Mezolar Matrix transdermal patch should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day. To convert paediatric patients from oral or parenteral opioids to Fentanyl transdermal patch, refer to Table 1 and Table 2.
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 Mezolar Matrix transdermal patch 12.5 microgram/hour. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its
equivalent) to Mezolar Matrix transdermal. The conversion schedule could not be used to convert from Mezolar Matrix transdermal into other opioids, as overdosing could then occur.
The analgesic effect of the first dose of Mezolar Matrix transdermal patch will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Mezolar Matrix transdermal patch, 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.
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 Mezolar Matrix transdermal patch therapy or up-titration of the dose (see also section 4.4).
Dose titration and maintenance therapy
If the analgesic effect of Mezolar Matrix transdermal patch 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 12.5 microgram/hour steps.
Hepatic and renal impairment
Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).
Method of administration For transdermal use.
Directly after removal from the pack and the release liner, the Mezolar Matrix transdermal patch is applied to a non-hairy area of skin on the upper body (chest, back, upper arm).
For use in children: There are no safety and pharmacokinetic data available for other application sites.
In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.
To remove hair, scissors should be used instead of razors.
Prior to application, the skin should be carefully washed with clean water (no cleaning agents) and thoroughly dried. The transdermal patch is then applied using slight pressure with the palm of the hand for approximately 30 seconds. The skin area to which the patch is applied should be free of microlesions (e.g. due to irradiation or shaving) and skin irritation.
As the transdermal patch is protected by an outer waterproof backing film, it can also be worn while showering.
If progressive dose increases are made, the active surface area required may reach a point where no further increase is possible.
Duration of administration
The patch should be changed after 72 hours. If an earlier change becomes necessary in individual cases, no change should be made before 48 hours have elapsed, otherwise a rise in mean fentanyl concentrations may occur. A new skin area must be selected for each application. A period of 7 days should be allowed to elapse before
applying a new patch to the same area of skin. The analgesic effect may persist for some time after removal of the transdermal patch.
If traces of the transdermal patch remain on the skin after removal of the patch, these can be cleaned off using copious amounts of soap and water. No alcohol or other solvents must be used for cleaning as these may penetrate the skin due to the effect of the patch.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Acute or postoperative pain, since dosage titration is not possible during short term use and because serious and life-threatening hypoventilation could result
- Severe impairment of the central nervous system
- Severe respiratory depression
4.4 Special warnings and precautions for use
Patients who have experienced serious adverse events should be monitored for at least 24 hours after Fentanyl transdermal patch removal or more as clinical symptoms dictate because serum fentanyl concentrations decline gradually and are reduced by about 50% 17 (range 13-22) hours later.
Mezolar Matrix transdermal patch should be kept out of reach of children at all times before and after use.
The transdermal patch should not be cut, since no data is available on the quality, efficacy and safety of such divided patches. A patch that has been divided, cut, or damaged in any way should not be used.
It is not possible to ensure the interchange ability 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.
Breakthrough pain
Studies have shown that almost all patients, despite treatment with a fentanyl transdermal patch, require supplemental treatment with potent rapid-release medicinal products to arrest breakthrough-pain.
Respiratory depression
As with all potent opioids some patients may experience significant respiratory depression with fentanyl transdermal patches: patients must be observed for these effects. Respiratory depression may persist beyond the removal of the transdermal patch. The incidence of respiratory depression increases as the fentanyl dose is increased (see also section 4.9). CNS active substances may increase the respiratory depression (see section 4.5).
Chronic pulmonary disease
Fentanyl 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. Iatrogenic addiction following opioid administration is rare. Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of fentanyl transdermal patch 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.
Increased intracranial pressure
Fentanyl transdermal patches 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 transdermal patches should be used with caution in patients with brain tumors.
Cardiac disease
Fentanyl may cause bradycardia and should therefore be administered with caution to patients with bradyarrhythmias.
Opioids may cause hypotension, especially in patients with acute hypovolemia. Underlying, symptomatic hypotension and/or hypovolaemia should be corrected before treatment with fentanyl transdermal patches is initiated.
Hepatic impairment
Because fentanyl is metabolised to pharmacologically inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Mezolar Matrix, they should be observed carefully for signs of fentanyl toxicity and the dose of Mezolar Matrix reduced if necessary (see section 5.2).
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 kidneys. 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).
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 transdermal patch 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 the fentanyl transdermal pach 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, hot water bottles, electric blankets, heated water beds, heat or tanning lamps, intensive sunbathing, prolonged hot baths, saunas and hot whirlpool spa baths.
Serotonin syndrome
Caution is advised when fentanyl transdermal paches are coadministered 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 (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 Mezolar Matrix should be considered.
Accidental exposure by patch transfer
Accidental transfer of a fentanyl transdermal 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 older patients
Data from intravenous studies with fentanyl suggest that older patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the active substance than younger patients. If older patients receive Mezolar Matrix they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).
Paediatric population
Fentanyl transdermal patch should not be administered to opioid-naive paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of Mezolar Matrix administered.
Transdermal fentanyl has not been studied in children under 2 years of age. Mezolar Matrix should be administered only to opioid-tolerant children aged 2 years or older (see section 4.2). Mezolar Matrix 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 Mezolar Matrix (see section 4.2) and monitor adhesion of the patch closely.
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 Mezolar Matrix should be stopped.
Patients with myasthenia gravis
Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.
For disposal instructions see section 6.6.
4.5 Interaction with other medicinal products and other forms of interaction
Other central nervous system depressants
The concomitant use of other central nervous system depressants, including opioids, sedatives, anxiolytics, hypnotics, general anaesthetics, phenothiazines, tranquilizers, antipsychotics, 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 the above mentioned concomitant medicinal products requires special patient care and observation. Dose reduction of one or both medicinal products should be taken into consideration.
CYP3A4 inhibitors
Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.
The concomitant use of transdermal fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir, ketoconazole, itraconazole, 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.
CYP3A4 inducers
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)
Fentanyl transdermal patch 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, Mezolar Matrix should not be used within 14 days after discontinuation of treatment with MAOIs.
Serotonergic medicinal products
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.
4.6 Pregnancy and lactation
Pregnancy
There are no adequate data from the use of fentanyl transdermal patch in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown.fentanyl crosses the placenta. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl transdermal patch during pregnancy. Mezolar Matrix should not be used during pregnancy unless clearly necessary.
Use of fentanyl transdermal patch during childbirth is not recommended because it should not be used in the management of acute or postoperative pain (see section 4.4). Moreover, because fentanyl passes through the placenta, the use of Mezolar Matrix transdermal patch during childbirth might result in respiratory depression in the newborn infant.
Breast-feeding
Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breastfed infant. Breastfeeding should therefore be discontinued during treatment with Mezolar Matrix transdermal patch and for at least 72 hours after removal of the patch.
4.7 Effects on ability to drive and use machines
Mezolar Matrix may impair the mental and/or physical ability required to perform potentially hazardous tasks such as driving a car or operating machinery.
Patients stabilised on a specific dosage - without further interference from other medicinal products - will not necessarily be restricted. Caution is required especially at the beginning of treatment, at dosage increases as well as in connection with other medicinal products since the ability to drive and use machines may be impaired.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called ‘statutory defence’) if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely.
4.8 Undesirable effects
The safety of fentanyl transdermal patches was evaluated in 1854 adult and paediatric subjects who participated in 11 clinical trials (double-blind fentanyl transdermal patch [placebo or active control] and/or open label fentanyl transdermal patch [no control or active control]) used for the management of chronic malignant or non-malignant pain. These subjects took at least 1 dose of fentanyl transdermal patch 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 most serious undesirable effect of fentanyl is respiratory depression.
The ADRs reported with the use of fentanyl transdermal patches 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: > 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 data)
|
System organ class |
Adverse drug reactions | ||||
|
Frequency cat |
egory | ||||
|
Very Commo n |
Common |
Uncommon |
Rare |
Not known | |
|
Immune system disorders |
Hypersensitivity |
Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction | |||
|
System organ class |
Adverse drug reactions | ||||
|
Frequency cat |
egory | ||||
|
Very Commo n |
Common |
Uncommon |
Rare |
Not known | |
|
Metabolism and nutrition disorders |
Anorexia | ||||
|
Psychiatric disorders |
Insomnia, Depression, Anxiety, Confusional state 5 Hallucination |
Agitation, Disorientation, Euphoric mood | |||
|
Nervous system disorders |
Somnolence, Dizziness, Headache1 |
Tremor, Paraesthesia |
Hypoaesthesia, Convulsion (including clonic convulsions and grand mal convulsion), Amnesia | ||
|
Eye disorders |
Miosis | ||||
|
Ear and labyrinth disorders |
Vertigo | ||||
|
Cardiac disorders |
Palpitations, Tachycardia |
Bradycardia, Cyanosis |
Arrythmia | ||
|
Vascular disorders |
Hypertension |
Hypotension | |||
|
Respiratory, thoracic and mediastinal disorders |
Dyspnoea |
Respiratory depression, Respiratory distress |
Apnoea, Hypoventilatio n |
Bradypnoea, | |
|
Gastrointestin al disorders |
Nausea1, Vomiting1, Constipation1 |
Diarrhoea1,, Dry mouth, Abdominal pain, upper abdominal pain, Dyspepsia |
Ileus |
Subileus | |
|
Skin and subcutaneous tissue disorders |
Hyperhidrosis, Pruritus1, , Rash, Erythema |
Eczema, Allergic dermatitis, , Skin disorder, Dermatitis, Contact dermatitis | |||
|
System organ class |
Adverse drug reactions | ||||
|
Frequency cat |
egory | ||||
|
Very Commo n |
Common |
Uncommon |
Rare |
Not known | |
|
Musculoskelet al 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, Peripheral oedema, Asthenia, Malaise, Feeling cold |
Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivity , Drug withdrawal syndrome2, Pyrexia |
Application site dermatitis, Application site eczema | ||
1 see “paediatric subjects” below
2
see “description of selected adverse reactions” below As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can develop on repeated use of fentanyl transdermal patches (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 fentanyl transdermal patches during pregnancy (see section 4.6).
Paediatric Population
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, headache, vomiting, nausea, constipation, diarrhoea and pruritus.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme: www.mhra.gov.uk/yellowcard
4.9 Overdose
Symptoms
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 Mezolar Matrix transdermal 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-narcotisation after the patch is removed; repeated administration or a continuous infusion of naloxone may be necessary.
Reversal of the narcotic effect may result in acute onset of pain and release of catecholamines.
If the clinical situation warrants, a patent airway should be established and maintained, possibly with an oropharyngeal airway or endotracheal tube, and oxygen should be administered and respiration assisted or controlled, as appropriate.
Adequate body temperature and fluid intake should be maintained.
If severe or persistent hypotension occurs, hypovolemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: analgesics; opioids; phenylpiperidine derivatives ATC Code: N02AB03
Fentanyl is an opioid analgesic which interacts predominantly with the p-opioid receptor. Its principal therapeutic effects are analgesia and sedation. The serum concentrations of fentanyl that cause a minimal analgesic effect in
opioid-naive patients fluctuate between 0.3-1.5 ng/ml. The incidence of adverse effects increases when serum concentrations exceed 2 ng/ml. The concentration causing adverse reactions increases with the duration of exposure. The tendency to develop tolerance shows considerable inter-individual variety.
Paediatric population
The safety of transdermal fentanyl was evaluated in three open-label trials in 293 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 44 mg oral morphine per day was replaced by one fentanyl 12 microgram/hour transdermal patch. Starting dose of 25 microgram/hour and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg of oral morphine.
5.2 Pharmacokinetic properties
Following administration of Mezolar Matrix transdermal patch, fentanyl is continuously absorbed through the skin over a period of 72 hours. Due to the polymer matrix and the diffusion of fentanyl through the skin layers, the release rate remains relatively constant.
Absorption
After the first application of Mezolar Matrix transdermal patches, 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. The serum fentanyl concentrations attained are dependent on the Mezolar Matrix transdermal patch size. For all practical purposes by 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.
Distribution
The plasma protein binding for fentanyl is 84 %.
Biotransformation
Fentanyl is metabolised primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.
Elimination
When treatment with Mezolar Matrix transdermal patches is withdrawn, serum fentanyl concentrations decline gradually, falling approximately 50 % in 13-22 hours in adults or 22-25 hours in children, respectively. Continued absorption of fentanyl from the skin accounts for a slower reduction in serum concentration 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 active substance. About 9 % of the dose is recovered in the faeces, primarily as metabolites.
Pharmacokinetics in special populations
Older people
Data from intravenous studies with fentanyl suggest that older patients may have reduced clearance, a prolonged half-life, and they may be more sensitive to the active substance than younger patients. In a study conducted with a fentanyl transdermal patch, healthy older subjects had fentanyl pharmacokinetics which did not differ significantly from healthy young subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours. Older patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.2).
Paediatric population
Adjusting for body weight, clearance (L/hour/Kg) in paediatric patients appears to be 82% higher in children 2 to 5 years old and 25% higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are likely to have the same clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.
Hepatic impairment
In a study conducted with patients with hepatic cirrhosis, the pharmacokinetics of a single 50 microgram/hour application were assessed. Although tmax and ti/2 were not altered, the mean plasma Cmax and AUC values increased by approximately 35% and 73%, respectively, in these patients. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of Mezolar Matrix reduced if necessary (see section 4.4).
Renal impairment
Data obtained from a study administering intravenious fentanyl in patients undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population. If patients with renal impairment receive Mezolar Matrix, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.4).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In a rat study fentanyl did not influence male fertility. Studies with female rats revealed reduced fertility and enhanced embryonal mortality. More recent studies showed that effects on the embryo were due to maternal toxicity and not to direct effects of the substance on the developing embryo. There were no indications for teratogenic effects in studies in two species. In a study on pre- and postnatal development the survival rate of offspring was significantly reduced at doses which slightly reduced maternal weight. This effect could either be due to altered maternal care or a direct effect of fentanyl on the pups. Effects on somatic development and behaviour of the offspring were not observed.
In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumours at subcutaneous doses up to 33 microgram/kg/day in males
or 100 microgram/kg/day in females. The overall exposure (AUC0-24 h) achieved in this study was <40% of that likely to be achieved clinically at the dose strength of 100 microgram/hour fentanyl transdermal patch, due to the maximum tolerated plasma concentrations in rats.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Release liner:
Poly(ethylene terephthalate) foil, siliconised Self-adhesive matrix layer:
Acrylic-vinylacetate copolymer Backing film:
Poly(ethylene terephthalate) foil Printing ink
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package
6.5 Nature and contents of container
Each transdermal patch is packed in a separate child resistant sachet made of PET/Al/PE.
Packs with 1, 2, 3, 4, 5, 7, 8, 10, 14, 16 and 20 transdermal patches. Hospital packs with 5 transdermal patches.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Please refer to section 4.2 for instructions on how to apply the patch.
Significant quantities of fentanyl remain in the transdermal patches even after use. Used transdermal patches should be folded with the adhesive surfaces inwards and due to safety and environmental reasons, discarded safely out of the reach of children and in accordance with local requirements.
Any unused medicinal product should be discarded safely or returned to the pharmacy.
Wash hands with water only after applying or removing the patch.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR.
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04416/0846
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/08/2013
10 DATE OF REVISION OF THE TEXT
15/08/2014