OPIODUR 12 MICROGRAMS/HOUR TRANSDERMAL PATCH

Active substance: FENTANYL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Opiodur 12 micrograms/hour transdermal patch

2.
QUALITATIVE AND QUANTITATIVE
COMPOSITION
Each Opiodur 12 micrograms/ hour transdermal patch contains 1.375 mg of fentanyl in
a patch size of 5cm2, releasing 12 micrograms of fentanyl per hour.
Excipients(s) with known effect:
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Transdermal Patch

Opiodur transdermal patch is a rectangular, tan coloured patch placed between
two oversized, transparent protective layers which must be removed prior to
the patch application.
The patches will be imprinted:
“Fentanyl 12 μg/h” in red ink

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Adults
This product is indicated in 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
It is not possible to ensure the interchangeability of different fentanyl containing
transdermal patch product in individual patients. Therefore, it should be emphasised
that patients should not be changed from one fentanyl containing product to another
without specific counselling on the change from their healthcare professionals.
Initial dose selection
The appropriate initiating dose of fentanyl should be based on the patient’s current
opioid use. It is recommended that fentanyl be used in patients who have demonstrated
opioid tolerance. Other factors to be considered are the current general condition and
medical status of the patient, including body size, age, and extent of debilitation as well
as degree of opioid tolerance.
Adults
Opioid-tolerant patients
To convert opioid-tolerant patients from oral or parenteral opioids to fentanyl refer to
Equianalgesic potency conversion below. The dosage may subsequently be titrated
upwards or downwards, if required, in increments of either 12 or 25 mcg/hr to achieve
the lowest appropriate dose of fentanyl depending on response and supplementary
analgesic requirements.
Opioid-naive patients
In strong opioid-naive patients, the normal initial fentanyl dosage should not exceed 25
mcg/h.
Clinical experience with fentanyl is limited in opioid-naïve patients. In the
circumstances in which therapy with fentanyl 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 with a release rate of 25 mcg/hr.
Patients can then be converted to fentanyl 25 mcg/hr. 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 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).
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 to 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 for opioid rotation (conversion ratio
of oral morphine to transdermal fentanyl equal to 150:1)
b) using Table 3 for patients 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
Morphine
Hydromorphone
Methadone
Oxycodone
Levorphanol
Oxymorphine
Diamorphine
Pethidine
Codeine
Buprenorphine
Ketobemidone

Equianalgesic doses (mg)
Parenteral i.m
Oral
10
30-40
1.5
7.5
10
20
10-15
20-30
2
4
1
10 (rectal)
5
60
75
200
0.4
0.8 (sublingual)
10
20-30

Table 2: Recommended starting dosage of transdermal fentanyl based on daily
oral morphine dosage1 (for patients stabilised on oral morphine or immediate
release opioid for several weeks and who need opioid rotation)
Transdermal fentanyl release (micrograms/h)
Oral morphine dose (mg/24 h)
< 44
45-134
135-224
225-314
315-404
405-494
495-584
585-674
675-764
765-854
855-944
945-1034
1035-1124

12
25
50
75
100
125
150
175
200
225
250
275
300

Table 3: Recommended starting dosage of transdermal fentanyl based on daily
oral morphine dosage (for patients on stable and well tolerated opioid therapy
for long periods and who need opioid rotation)

Oral morphine dose
(mg/24 h)
< 60
60-89
90-149
150-209
210-269
270-329
330-389
390-449
450-509
510-569
570-629
630-689
690-749

Transdermal Fentanyl
release (µg/h)
12
25
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 Opiodur 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 Opiodur 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 Opiodur after 48 hours may
be necessary.
Patches with a release rate of 12 micrograms/hour are available and are appropriate
for dose titration in the lower dosage area. If analgesia is insufficient at the end of the
initial application period, the dose may be increased after 3 days, until the desired
effect is obtained for each patient. Additional dose adjustment should normally be
performed in 12 micrograms/hour or 25 micrograms/hour increments, although the
supplementary analgesic requirements and pain status of the patient should be taken
into account.
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 Fentanyl dose exceeds 300
micrograms/hour.
If higher dosages than 500 mg morphine-equivalent are needed, a reassessment of
opioid-therapy is recommended.
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 discontinuation of 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.
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.
Dose titration and maintenance
If the analgesic effect of Opiodur 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 use more patches. Dose
adjustments should be done in 12 mcg/hour steps.
Use in elderly patients
Data from intravenous studies with fentanyl suggest that elderly patients may have
reduced clearance, a prolonged half-life and they may be more sensitive to the drug
than younger patients. Studies of fentanyl in elderly patients demonstrated fentanyl
pharmacokinetics which did not differ significantly from young patients although
serum concentrations tended to be higher.
Elderly, cachectic, or debilitated patients should be observed carefully for signs of
fentanyl toxicity and the dose reduced if necessary (see sections 4.4 and 5.2).
Hepatic and renal impairment
Patients with impaired hepatic or renal function should be observed carefully and the
dose reduced if necessary (see section 4.4).
Paediatric population
Generally Opiodur should be administered only to opioid-tolerant paediatric
patients (ages 2 to 16) who are already receiving at least 30 mg oral morphine
equivalents per day. To convert pediatric patients from oral or parenteral opioids to
Opiodur, refer to Equianalgesic potency conversion (Table 1), and Recommended
Opiodur dose based upon daily oral morphine dose (Table 4).
Table 4: Recommended Opiodur dose based upon daily oral morphine dose1

Oral 24-hour Morphine (mg/day)
For Paediatrics2
30-44

2

12

45-134
1

Fentanyl Dose (µg/h)
For Paediatrics
25

In clinical trials these ranges of daily oral morphine doses were used as a basis for
conversion to Opiodur transdermal patches
Conversion to fentanyl transdermal patches doses greater than 25 mcg/h is the same for
adult and paediatric patients

For children who received more than 90 mg oral morphine a day, only limited
information is currently available from clinical trials. In the paediatric studies, the
required Opiodur dose was calculated conservatively: 30 mg to 45 mg oral morphine
per day or its equivalent opioid dose was replaced by one Opiodur 12 g/hr patch. It
should be noted that this conversion schedule for children only applies to the switch
from oral morphine (or its equivalent) to Opiodur. The conversion schedule could not
be used to convert from Opiodur into other opioids, as overdose could then occur.

μ

The analgesic effect of the first dose of Opiodur will not be optimal within the first 24
hours. Therefore, during the first 12 hours after switching to fentanyl transdermal
patches, 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)
Method of administration
Directly after removal from the pack and the release liner, the patch is 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.

4.3

Contraindications
Opiodur is contraindicated in patients with known hypersensitivity to fentanyl or to
the excipients in the patch.
Acute or postoperative pain, since dosage titration is not possible during short-term
use.

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 OPIODUR
REMOVAL AS CLINICAL SYMPTOMS DICTATE SERUM FENTANYL
CONCENTRATIONS DECLINE GRADUALLY AND ARE REDUCED BY
ABOUT 50% 17 (RANGE 13-22) HOURS LATER.
Concomitant use of mixed agonists/antagonists
The concomitant use of buprenorphine, nalbuphine or pentazocine is not
recommended (see also Section 4.5, Interaction with other medicinal products and
other forms of interaction).
Opiodur should be kept out of reach of children before and after use.
After exhibiting a serious adverse reaction a patient should be monitored for 24 hours
following removal of a transdermal patch due to the half-life of fentanyl (see section
5.2)
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.
Do not cut Opiodur patches. A patch that has been divided, cut, or damaged in any
way should not be used.
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 significant respiratory
depression with Opiodur and patients must be observed for these effects. Respiratory
depression may persist beyond the removal of the patch. The incidence of respiratory
depression increases as the Opiodur dose is increased (see section 4.9, concerning
respiratory depression).
CNS active drugs may increase 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.
Serotonin Syndrome
Caution is advised when Opiodur is co-administered with drugs that affect the
serotonergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with
the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake
Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and
with drugs which impair metabolism of serotonin (including Monoamine Oxidase
Inhibitors [MAOIs]). This may occur within the recommended dose.

Serotonin syndrome may include mental-status changes (e.g., agitation,
hallucinations, coma), autonomic instability (e.g, tachycardia, labile blood pressure,
hyperthermia), neuromuscular abnormalities (e.g. hyper-reflexia, incoordination,
rigidity), and/or gastrointestinal symptoms (e.g, nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, rapid discontinuation of Opiodur should be
considered.
Chronic pulmonary disease
In patients with chronic obstructive or other pulmonary diseases Opiodur may have
more severe adverse reactions; 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. 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
Opiodur may result in overdose and/or death.
Increased intracranial pressure
Opiodur 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.
Opiodur should be used with caution in patients in whom a cerebral tumour has been
detected.
Cardiac disease
Fentanyl may produce bradycardia and should therefore be administered with caution
to patients with bradyarrhythmias.
Opioids may cause hypotension, especially in patients with 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 inactive metabolites in the liver, hepatic
impairment might delay its elimination. If patients with hepatic impairment receive
Opiodur they should be observed carefully for signs of fentanyl toxicity and the dose
of Opiodur 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 kidney. Data obtained with
intravenous fentanyl in patients with renal failure suggest that the volume of
distribution of fentanyl may be changed by dialysis. This may affect serum
concentrations. If patients with renal impairment receive Opiodur 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 Opiodur 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 Opiodur system increased mean fentanyl AUC values by 120% and
mean Cmax values by 61%.
Patients should be advised to avoid exposing the Opiodur application site to direct
external heat sources such as heating pads, hot water bottles, electric blankets, heated
water beds, heat or tanning lamps, intensive sun bathing, prolonged hot baths, saunas
or hot whirlpool spa baths while wearing the patch, since there is potential for
temperature dependent increases in release of fentanyl from the patch.
Interactions with other Medicinal Products:
Interactions with CYP3A4 Inhibitors:
The concomitant use of Opiodur 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. Patients, especially those who are receiving Opiodur and
CYP3A4 inhibitors, should be monitored for signs of respiratory depression and
dosage adjustments should be made if warranted.
Use in elderly Patients
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. If elderly patients receive Opiodur they
should be observed carefully for signs of fentanyl toxicity and the dose reduced if
necessary (see section 5.2).
The use of fentanyl patches may lead to a positive doping test. The use of fentanyl
patches as a doping agent may be hazardous to the health.
Patients with myasthenia gravis
Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when
treating patients with myasthenia gravis.
Lactation
As fentanyl is excreted into breast milk, breastfeeding should be discontinued during
treatment with Opiodur (see also section 4.6).
Paediatric patients

Opiodur 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 Opiodur transdermal fentanyl administered.
Opiodur was not studied in children under 2 years of age. Opiodur should be
administered only to opioid-tolerant children age 2 years or older (see Section 4.2).
Opiodur 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 Opiodur (see Section 6.6) and monitor adhesion of the patch
closely.

4.5

Interaction with other medicinal products and other forms of
interaction
The concomitant use of other CNS depressants, including opioids, sedatives,
hypnotics, general anaesthetics, phenothiazines, tranquilizers, skeletal muscle
relaxants, sedating antihistamines, and alcoholic beverages may produce additive
depressant effects: hypoventilation, hypotension and profound sedation, coma or
death may occur. Therefore, the use of any of these drugs concomitantly with
Opiodur requires special patient care and observation.
Fentanyl, a high clearance active substance, is rapidly and extensively metabolised
mainly by CYP3A4.
The concomitant use of transdermal fentanyl with cytochrome P450 (CYP3A4)
inhibitors (e.g. ritonavir, ketoconazole, itraconazole, macrolide antibiotics) may result
in an increase in fentanyl plasma concentrations, which could increase or prolong
both the therapeutic effects and the adverse effects, and which may cause severe
respiratory depression. In this situation, special patient care and observation are
appropriate. The concomitant use of CYP3A4-inhibitors and transdermal fentanyl is
not recommended, unless the patient is closely monitored (see section 4.4).
The concomitant use with CYP3A4 inducers (e.g. rifampicin, carbamazepine,
phenobarbital, phenytoin) could result in a decrease in fentanyl plasma concentrations
and a decreased therapeutic effect. This may require a dose adjustment of transdermal
fentanyl. After stopping the treatment of a CYP3A4 inducer, the effects of the inducer
decline gradually and may result in a fentanyl plasma increase concentration which
could increase or prolong both the therapeutic and adverse effects, and may cause
serious respiratory depression. In this situation, careful monitoring and dose
adjustment should be made if warranted
Monoamine Oxidase Inhibitors (MAOI)
Opiodur 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, Opiodur should not be used within 14 days
after discontinuation of treatment with MAOIs.
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 dependant patients (see also section 4.4).

4.6

Fertility, pregnancy and lactation
There are no adequate data from the use of Opiodur 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 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 Opiodur during pregnancy.
Opiodur should not be used in pregnancy unless clearly necessary.
Use of Opiodur 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 Opiodur during childbirth
might result in respiratory depression in the newborn infant.
Fentanyl is excreted into breast milk and may cause sedation and respiratory
depression in the breast-fed infant. Breastfeeding should therefore be discontinued
during treatment with Opiodur and for at least 72 hours after the removal of the patch.

4.7

Effects on ability to drive and use machines
Opiodur may impair mental and/or physical ability required for the performance of
potentially hazardous tasks such as driving a car or operating machinery. This has to
be expected especially at the beginning of treatment, at any change of dosage as well
as in connection with alcohol or antipsychotics. Patients stabilised on a specific
dosage will not necessarily be restricted. Therefore, patients should consult their
physician as to whether driving or use of machines is reasonable.

4.8

Undesirable effects
The safety of Opiodur was evaluated in 1854 subjects who participated in 11 clinical
trials (double-blind Opiodur [placebo or active control] and/or open label Opiodur [no
control or active control]) used for the management of chronic malignant or nonmalignant pain.
These subjects took at least 1 dose of Opiodur 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 Opiodur 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); and Not known (cannot be estimated
from the available clinical trial data).

System Organ
Class

Very Common

Adverse Drug Reactions
Frequency Category
Common
Uncommon
Rare

Not Known
Anaphylactic
shock,
Anaphylactic
reaction,
Anaphylactoid
reaction

Immune System
Disorders

Hypersensitivity

Metabolism and
Nutrition
Disorders

Anorexia

Psychiatric
Disorders

Depression,
Anxiety,
Confusional
state,
Hallucination

Agitation,
Disorientation,
Euphoric mood

Tremor,
Paraesthesia

Hypoaesthesia,
Convulsion
(including clonic
convulsions and
grand mal
convulsion),
Amnesia

Insomnia,
Somnolence.

Nervous System Dizziness,
Headache
Disorders

Miosis

Eye Disorders
Ear and
Labyrinth
Disorders
Cardiac
Disorders
Vascular
Disorders
Respiratory,
Thoracic and
Mediastinal
Disorders
Nausea,
Gastrointestinal
Vomiting,
Disorders
Constipation

Vertigo
Palpitations,
Tachycardia

Bradycardia,
Cyanosis

Hypertension

Hypotension

Dyspnoea

Respiratory
depression,
Respiratory
distress

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

Apnoea,
Bradypnoea,
Hypoventilation

Subileus

System Organ
Class

Skin and
Subcutaneous
Tissue Disorders

Musculoskeletal
and Connective
Tissue Disorders
Renal and
Urinary
Disorders
Reproductive
System and
Breast
Disorders

General
Disorders and
Administration
Site Conditions

Very Common

Adverse Drug Reactions
Frequency Category
Common
Uncommon
Rare

Hyperhidrosis,
Pruritus, Rash,
Erythema

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

Muscle spasms

Not Known

Muscle twitching

Urinary retention
Erectile
dysfunction,
Sexual
dysfunction
Application site
reaction,
Influenza like
Fatigue, Oedema illness, Feeling of
body temperature Application site
peripheral,
dermatitis,
change,
Asthenia,
Application site
Malaise, Feeling Application site
hypersensitivity, eczema
cold
Drug withdrawal
syndrome
Pyrexia.

Paediatric Subjects
The adverse event profile in children and adolescents treated with Opiodur 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 Opiodur use in children as young as 2 years old when used as directed. Very
common adverse events reported in paediatric clinical trials were fever, vomiting, and
nausea.
As with other opioid analgesics, tolerance, physical dependence, and psychological
dependence can develop on repeated use of Opiodur (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 [Invented name] 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 Opiodur during pregnancy (see
section 4.6).
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 professional are asked to report any suspected adverse
reactions via the Yellow Card Scheme at:
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 patch and physically or verbally stimulating the patient. These actions
can be followed by administration of a specific opioid antagonist such as naloxone.
Respiratory depression following an overdose may outlast the duration of action of
the opioid antagonist. The interval between IV antagonist doses should be carefully
chosen because of the possibility of re-narcotization after the patch is removed;
repeated administration or a continuous infusion of naloxone may be necessary.
Reversal of the narcotic effect may result in acute onset of pain and release of
catecholamines.
If the clinical situation warrants, a patent airway should be established and
maintained, possibly with an oropharyngeal airway or endotracheal tube, and oxygen
should be administered and respiration assisted or controlled, as appropriate.
Adequate body temperature and fluid intake should be maintained.
If severe or persistent hypotension occurs, hypovolemia should be considered, and the
condition should be managed with appropriate parenteral fluid therapy.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: opioids; phenylpiperidine derivatives, ATC Code:
N02AB03
Fentanyl is an opioid analgesic which interacts predominantly with the µ-receptor. Its
principal therapeutic effects are analgesia and sedation. The serum concentrations of
fentanyl that cause a minimal analgesic effect in opioid-naïve 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 Opiodur 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 45 mg oral morphine per
day was replaced by one Opiodur 12 mcg/hour transdermal patch. Starting dose of 25
mcg/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
Following administration of Opiodur, 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 Opiodur, serum fentanyl concentrations increases
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 metabolised primarily in the liver via CYP3A4. The major metabolite, nor
fentanyl, is inactive.
Elimination
When treatment with Opiodur, 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 groups
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.
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 (see sections 4.2 and 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.

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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Overlay liner
Polyethylene terephthalate film with fluorocarbon release coating.
Backing Layer
Pigmented polyethylene terephthalate/ethylene vinyl acetate copolymer film
Drug adhesive Layer
Silicone adhesive (polydimethylsiloxane, silicate resin)
Polydimethylsiloxane
Rate controlling membrane
Ethylene vinyl acetate copolymer film
Skin adhesive Layer
Silicone adhesive (polydimethylsiloxane, silicate resin)
Polydimethylsiloxane
Release liner
Polyethylene terephthalate film with fluorocarbon release coating
Printing ink
Red ink

6.2

Incompatibilities
To prevent interference with the adhesive properties of the patch, no creams, oils,
lotions or powder should be applied to the skin area when the patch is applied.

6.3

Shelf life
3 years

6.4

Special precautions for storage
Do not store above 25°C.
Store in the original package in order to protect from moisture.

6.5

Nature and contents of container
The product is packaged between two sheets of a multi-laminate pouching material,
containing aluminium foil as the primary barrier component and a layer of ionomer
resin attached to the aluminium layer, and in direct contact with the product. The two
sheets of the multilaminate film are sealed together at the edges so as to enclose the
product in a child resistant sachet.
Pack sizes:
Package containing 3 individually sealed transdermal patches
Package containing 4 individually sealed transdermal patches
Package containing 5 individually sealed transdermal patches
Package containing 8 individually sealed transdermal patches
Package containing 9 individually sealed transdermal patches
Package containing 10 individually sealed transdermal patches
Package containing 16 individually sealed transdermal patches
Package containing 19 individually sealed transdermal patches
Package containing 20 individually sealed 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. Any
unused medicinal product and any used transdermal patches, folded with the adhesive
surfaces inwards, should be discarded or returned to the pharmacy, according to the
local requirements, as applicable.

7

MARKETING AUTHORISATION HOLDER
Pfizer Limited,
Ramsgate Road,
Sandwich,
Kent CT13 9NJ.

8

MARKETING AUTHORISATION NUMBER(S)
PL 00057 / 1474

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/06/2013

10

DATE OF REVISION OF THE TEXT
06/11/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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