Fentanyl Orion
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
[FentanylOrion]12 micrograms/hour transdermal patch
[Fentanyl Orion] 25 micrograms/hour transdermal patch
[Fentanyl Orion] 50 micrograms/hour transdermal patch
[Fentanyl Orion] 75 micrograms/hour transdermal patch
[Fentanyl Orion] 100 micrograms/hour transdermal patch
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
[Fentanyl Orion] 12 micrograms/hour: Each patch releases 12.5 micrograms fentanyl per hour. Each transdermal patch of 4.25 cm2contains 2.55 mg fentanyl.
Contains soya oil.
[Fentanyl Orion] 25 micrograms/hour: Each patch releases 25 micrograms fentanyl per hour. Each transdermal patch of 8.5 cm2contains 5.1 mg fentanyl.
Contains soya oil.
[Fentanyl Orion] 50 micrograms/hour: Each patch releases 50 micrograms fentanyl per hour. Each transdermal patch of 17 cm2contains 10.2 mg fentanyl.
Contains soya oil.
[Fentanyl Orion] 75 micrograms/hour: Each patch releases 75 micrograms fentanyl per hour. Each transdermal patch of 25.5 cm2contains 15.3 mg fentanyl.
Contains soya oil.
[Fentanyl Orion] 100 micrograms/hour: Each patch releases 100 micrograms fentanyl per hour. Each transdermal patch of 34 cm2contains 20.4 mg fentanyl.
Contains soya oil.
For the full list of excipients, see section 6.1.
Transdermal patch
[Fentanyl Orion] 12 micrograms/hour: Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 12µg/h”.
[Fentanyl Orion] 25 micrograms/hour: Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 25µg/h”.
[Fentanyl Orion] 50 micrograms/hour: Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 50µg/h”.
[Fentanyl Orion] 75 micrograms/hour: Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 75µg/h”.
[Fentanyl Orion] 100 micrograms/hour: Opaque, colourless, rectangular shaped patch with round corners and imprint on the backing foil: “fentanyl 100µg/h”.
Adults:
[Fentanyl Orion] is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.
Children:
[Fentanyl Orion] is indicated in long-term management of severe chronic pain in children receiving opioid therapy from 2 years of age.
4.2 Posology and method of administration
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.
Posology
Patients receiving opioid treatment for the first time
For initial dosingpatches with a release rate of 12.5 micrograms/hour should be used. In very elderly or weak patients, it is not recommended to initiate an opioid treatment with [Fentanyl Orion], 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 Orion] 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 correspond the 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 or 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.
|
|
Equianalgesic doses (mg) |
|
Oral |
|
||
|
Active substance |
Parenteral (i.m.) |
|
||||
|
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 need for opioid rotation)
|
Oral morphine dose (mg/24 h) |
Transdermal fentanyl release (micrograms/h) |
|
< 44 |
12.5 |
|
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 |
|
1,035-1,124 |
300 |
Table 3: Recommended initial doseof transdermal fentanyl based on daily oral morphine dose
(for patients on stable and well tolerated opioid therapy)
|
Oral morphine dose (mg/24 h) |
Transdermal fentanyl release (micrograms/h) |
|
< 60 |
12.5 |
|
60-89 |
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 |
By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/hour can be achieved.
The initial evaluation of the maximum analgesic effect of [Fentanyl Orion] 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 [Fentanyl Orion] 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 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 fentanyl after 48 hours may be necessary. The dose 12.5 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 25 micrograms/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. Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the fentanyldose exceeds 300 micrograms/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 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%. As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (nausea, vomiting, diarrhoea, anxiety and muscular tremor). Tables 2 and 3 should not be used to switch from transdermal fentanyl to a morphine treatment.
Method of administration
Directly after removal from the pack and the release liner, the patchis applied to a non-hairy area of skin on the upper body (chest, back, upper arm). 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.
Occasionally additional adhesion of the patch may be required.
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 its removal, 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.
Older people
Elderly should be observed carefully and the dose reduced if necessary (see sections 4.4 and 5.2).
Patients with hepatic and renal impairment
Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).
Paediatric population
Method of administration:
In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.
Children aged 16 years and above: follow adult dosage.
Children aged 2 to 16 years old:
Posology:
[Fentanyl Orion] 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 Orion], refer to Equianalgesic potency conversion (Table 1) and Recommended [Fentanyl Orion] dose based upon daily oral morphine dose (Table 4).
Table 4: Recommended [Fentanyl Orion] dose based upon daily oral morphine dose1
|
Oral morphine (mg/24 hour) |
Transdermal fentanyl Release (µg/hour) |
Transdermal fentanyl Absorption area (cm2) |
|
For paediatric patients2 |
||
|
30-44 |
12.5 |
4.25 |
|
45-134 |
25 |
8.5 |
1In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl transdermal patches
2For conversion to [Fentanyl Orion] doses greater than 25 micrograms/hour a conversion ratio of oral morphine to transdermal fentanyl of 150:1 is recommended (see 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 patch with a release rate of 12.5 micrograms /hour. 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 Fentanyl into other opioids, as overdosing could then occur.
The analgesic effect of the first dose of fentanyl patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to fentanyl, 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 fentanyl therapy or up-titration of the dose (see also section 4.4).
Dose titration and maintenance:
If the analgesic effect of [Fentanyl Orion] 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 micrograms/hour steps.
-
Hypersensitivity to the active substance, soya, peanuts 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 or life-threatening hypoventilation could result.
-
Severe impairment of central nervous system.
-
Severe respiratory depression.
4.4 Special warnings and precautions for use
The product should be used only as part of an integrated treatment of pain in cases where the patient is adequately assessed medically, socially and psychologically.
Treatment with [Fentanyl Orion]should only be initiated by an experienced physician familiar with the pharmacokinetics of fentanyl transdermal patches and the risk for severe hypoventilation.
Patients who have experienced serious adverse events should be monitored for at least 24 hours after [Fentanyl Orion] 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.
In chronic non-cancer pain, it might be preferable to initiate the treatment with immediate-release strong opioids (e.g. morphine) and to prescribe fentanyl transdermal patch after determination of the efficacy and the optimal dosage of the strong opioid.
The transdermal patch should not be cut, since no information 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.
If higher dosages than 500 mg morphine-equivalent are needed, a reassessment of opioid-therapy is recommended.
The most common adverse reactions following administration at usual doses are drowsiness, confusion, nausea, vomiting and constipation. The first of these are transient and their cause should be investigated if symptoms persist. Constipation, on the other hand, does not stop if treatment continues. All of these effects can be expected and should, therefore, be anticipated in order to optimise treatment, especially constipation. Corrective treatment may often be required (see section 4.8).
The concomitant use ofbarbituric acid derivatives, buprenorphine, nalbuphine or pentazocine is not recommended (see also section 4.5).
[Fentanyl Orion] should be kept out of reach of children before and after use.
Breakthrough pain
Studies have shown that almost all patients, despite treatment with a fentanyl 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 respiratory depression with fentanyl, and patients must be observed for this effect. 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). CNS active substances may worsen the respiratory depression (see section 4.5).
In patients with existing respiratory depression, fentanyl should only be used with caution and at a lower dose.
Chronic pulmonary disease
In patients with chronic obstructive or other pulmonary diseases fentanyl may have more severe adverse reactions, in such patients opioids may decrease respiratory drive and increase airway resistance.
Drug dependence
Tolerance and physical and psychological dependence may develop upon repeated administration of opioids, but is rare in treatment of cancer related pain. 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 fentanyl may result in overdose and/or death.
Increased intracranial pressure
Fentanyl 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 tumours.
Cardiac disease
Opioids may cause hypotension, especially in patients with hypovolaemia. Caution should therefore be taken in treatment of patients with hypotension and/or patients with hypovolaemia. Underlying, symptomatic hypotension and/or hypovolaemia should be corrected before treatment with fentanyl transdermal patches is initiated.
Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias.
Gastrointestinal tract
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Patients should be advised to take measures to prevent constipation and prophylactic laxative use may be considered in some situations. Extra caution should be used in patients with chronic constipation. If paralytic ileus is present or suspected, treatment with fentanyl should be stopped.
Impaired liver function
Fentanyl is metabolised to inactive metabolites in the liver, so patients with hepatic disease might have a delayed elimination. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
Renal impairment
Less than 10% of fentanyl is excreted unchanged by the kidneys, and unlike morphine, there are no known active metabolites eliminated by the kidneys. Data obtained with intravenous fentanyl in patients with renal failure suggest that the volume of distribution of fentanyl may be changed by dialysis. This may affect serum concentrations. If patients with renal impairment receive transdermal fentanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
Serotonin syndrome
Caution is advised when fentanyl is coadministered with drugs that affect the serotoninergic
neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant
use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin
Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin
(including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.
Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma),
autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular
abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, treatment with Fentanyl Orion should be discontinued.
Patients with fever/external heat
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 the [Fentanyl Orion] system increased mean fentanyl AUC values by 120% and mean Cmaxvalues by 61%.
All patients should be advised to avoid exposing the [Fentanyl Orion] 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.
Interactions with CYP3A4 Inhibitors
The concomitant use of transdermal fentanyl and CYP3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole, 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. 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 fentanyl and CYP3A4 inhibitors, should be monitored for signs of respiratory depression and dosage adjustments should be made if warranted.
Concomitant use of mixed agonists/antagonists
The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see also 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).
Older people
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. However, studies of fentanyl transdermal patch in elderly patients demonstrated fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly or cachectic patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).
Paediatric population
[Fentanyl Orion] 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 fentanyl administered (see Table 4 in section 4.2).
Fentanyl transdermal patches have not been studied in children under 2 years of age. [Fentanyl Orion] should be administered only to opioid-tolerant children age 2 years or older (see section 4.2). [Fentanyl Orion] 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 [Fentanyl Orion] (see section 4.2) and monitor adhesion of the patch closely.
Lactation
As fentanyl is excreted into breast milk, lactation should be discontinued under treatment with [FentanylOrion] (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.
4.5 Interaction with other medicinal products and other forms of interaction
The concomitant use of barbituric acid derivatives should be avoided, since the respiratory depressing effect of fentanyl may be increased.
The concomitant use of other CNS depressants may produce additive depressant effects and hypoventilation, hypotension as well as profound sedation, coma or death may occur. The CNS depressants mentioned above include:
-
opioids
-
anxiolytics and tranquilizers
-
hypnotics
-
general anaesthetics
-
phenothiazines
-
skeletal muscle relaxants
-
sedating antihistamines
-
alcoholic beverages.
Therefore, the use of any of the above mentioned concomitant medicinal products and active substancesrequire observation of the patient.
Interactions with CYP3A4 inhibitors
Fentanyl, a high clearance drug, is rapidly and extensively metabolized mainly by CYP3A4. The concomitant use of fentanyl with cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. ritonavir, ketoconazole, itraconazole, 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. Therefore, the concomitant use of transdermal fentanyl and CYP3A4 inhibitors is not recommended unless the patient is closely monitored (see also section 4.4).
Interactions with 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 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 Orion] should not be used within 14 days after discontinuation of treatment with MAOIs.
Serotoninergic agents
Coadministration of fentanyl with a serotoninergic 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).
4.6 Fertility, pregnancy and lactation
Pregnancy
The safety of fentanyl in pregnancy has not been established. Studies in animals have shown 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 early human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl during pregnancy.Fentanyl should only be used during pregnancy when clearly necessary.
Use of fentanyl 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 fentanyl during childbirth might result in respiratory depression in the newborn infant.
Breastfeeding
Fentanyl is excreted in human milk and may cause sedation and respiratory depression in the breast-fed infant. Lactation should therefore be discontinued during treatment and for at least 72 hours after the removal of [Fentanyl Orion] (see also section 4.4).
4.7 Effects on ability to drive and use machines
Fentanylhas major influence on the ability to drive and use machines. This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilizers. Patients stabilized on a specific dosage will not necessarily be restricted. Therefore, patients should consult their physician as to whether driving or use of machines is permitted.
The safety of fentanyl was evaluated in 1,854 subjects who participated in 11 clinical trials (double-blind fentanyl [placebo or active control] and/or open label 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 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 fentanyl from these clinical trials, including the above-mentioned ADRs, and from post-marketing experiences are listed below.
The following frequencies are used for the description of the occurrence of adverse reactions:
Very common (≥ 1/10), Common (≥ 1/100, < 1/10), Uncommon (≥ 1/1,000, < 1/100), Rare (≥ 1/10,000, < 1/1,000), Very rare (< 1/10,000), Not known (cannot be estimated from the available data)
|
System organ class |
Adverse drug reactions |
||||
|
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 |
|
|
|
Eye disorders |
|
|
|
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 |
Application site dermatitis, application site eczema |
|
As with other opioid analgesics, 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 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 during pregnancy (see section 4.6).
Paediatric population
The adverse event profile in children and adolescents treated with fentanyl transdermal patches 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. There does not appear to be any paediatric-specific risk associated with fentanyluse 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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Symptoms
The symptoms of fentanyl overdose are an extension of its pharmacological actions, e.g. lethargy, coma, respiratory depression with Cheyne-Stokes respiration and/or cyanosis. Other symptoms may be hypothermia, decreased muscle tonus, bradycardia, hypotension. Signs of toxicity are deep sedation, ataxia, miosis, convulsions and respiratory depression, which is the main symptom.
Treatment
For management of respiratory depression immediate countermeasures should be started, including removing the patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone.
A starting dose of 0.4-2 mg naloxone hydrochloride i.v. is recommended for adults. If needed, a similar dose can be given every 2 or 3 minutes, or be administered as continued infusion as 2 mg in 500 ml sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution. The infusion rate should be adjusted according to previous bolus injections and the individual response of the patient. If intravenous administration is impossible, naloxone hydrochloride can also be given intramuscularly or subcutaneously. Following intramuscular or subcutaneous administration the onset of action will be slower compared with intravenous administration. Intramuscular administration will give a more prolonged effect than intravenous administration. Respiratory depression due to overdose can persist longer than the effect of the opioid antagonist. Reversing the narcotic effect can give rise to acute pain and release of catecholamines. Intensive care unit treatment is important, if required by the patient’s clinical condition. 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: opioids, phenylpiperidine derivatives, ATC code: N02AB03
Fentanyl is an opioid analgesic which interacts predominantly with the -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; an increased incidence of adverse reactions is observed if serum levels exceed 2 ng/ml.
Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. The tendency to develop tolerance varies considerably between individuals.
The safety of fentanyl transdermal patches were 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 patch with a release rate of 12.5 micrograms /hour . Starting doses of 25 micrograms /hour 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.
5.2 Pharmacokinetic properties
Absorption
Following administration of [Fentanyl Orion], 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.
After the first application of [Fentanyl Orion], 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 dependant on the fentanyl 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 metabolized primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.
Elimination
When treatment with [Fentanyl Orion] is withdrawn, serum fentanyl concentrations decline gradually, falling approximately 50% in 13‑22 hours in adults or22‑25 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.
Pharmacokineticsin special groups
Elderly and debilitated patients may have reduced clearance of fentanyl leading to prolonged terminal half life. In patients with renal or hepatic impairment, clearance of fentanyl may be altered because of changes of plasma proteins and metabolic clearance resulting in increased serum concentrations.
Paediatric population
Adjusting for body weight, clearance (L/h/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.
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.
Animal studies have shown reduced fertility and increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.
Long-term carcinogenicity studies have not been performed.
Matrix components:
Aloe vera leaf extract oil on the basis of soya oil tocopherol acetate
Pentaerythritol ester of hydrogenated rosin
Poly (2‑ethylhexylacrylate,vinyl acetate) (50:50)
Release liner:
Polyester foil
Backing foil with imprint:
Polyethylene terephthalate foil, printing colour
Not applicable.
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Each transdermal patch is packed individually into a sealed child resistant sachet. The sachet is composed of different layers, polyester, aluminium foil and surlyn and is tightly sealed.
4, 5, 8, 10, 16, 20 transdermal patches.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
High quantities of fentanyl remain in the transdermal patches even after use. Used patches should be folded so that the adhesive side of the patch adheres to itself and then they should be safely discarded. Unused patches should be returned to the (hospital) pharmacy.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
[To be completed nationally]
10. DATE OF REVISON OF THE TEXT
25 February 2016