Final CSP for Fentanyl patches (Durogesic)

PSUR Worksharing Procedure

SUMMARY OF PRODUCT CHARACTERISTICS

4.3 Contraindications

Durogesic is contraindicated in patients with known hypersensitivity to

fentanyl or to the excipients present 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

DUROGESIC SHOULD NOT BE USED IN THE MANAGEMENT OF

ACUTE OR POSTOPERATIVE PAIN SINCE THERE IS NO
OPPORTUNITY FOR DOSE TITRATION DURING SHORT-TERM USE
AND BECAUSE SERIOUS OR LIFE-THREATENING
HYPOVENTILATION COULD RESULT.

PATIENTS WHO HAVE EXPERIENCED SERIOUS ADVERSE EVENTS

SHOULD BE MONITORED FOR UP TO 24 HOURS AFTER
DUROGESIC REMOVAL SINCE SERUM FENTANYL
CONCENTRATIONS DECLINE GRADUALLY AND ARE REDUCED
BY ABOUT 50% 17 (RANGE 13-22) HOURS LATER.

Durogesic should be kept out of reach of children before and after use.

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

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

Chronic Pulmonary Disease:

Durogesic 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.

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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 Durogesic may result in overdose
and/or death.

Increased Intracranial Pressure:

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

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

Opioids may cause hypotension, especially in patients with acute

hypovolaemia. Underlying, symptomatic hypotension and/or hypovolaemia
should be corrected before treatment with fentanyl transdermal patches is
initiated.

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

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

Fever/external heat application:

A pharmacokinetic model suggests that serum fentanyl concentrations may
increase by about one-third if the skin temperature increases to 40° C.
Therefore, patients with fever should be monitored for opioid side effects
and the Durogesic 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

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 Final CSP for Fentanyl patches (Durogesic)
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conducted in healthy adult subjects has shown that the application of heat
over the Durogesic system increased mean fentanyl AUC values by 120%
and mean Cmax values by 61%.

All patients should be advised to avoid exposing the Durogesic 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 other Medicinal Products:

Interactions with CYP3A4 Inhibitors:
The concomitant use of Durogesic 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
Durogesic 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 elderly patients
may have reduced clearance, a prolonged half-life, and they may be more
sensitive to the drug than younger patients. If elderly patients receive
Durogesic, they should be observed carefully for signs of fentanyl toxicity
and the dose reduced if necessary (see Section 5.2, Pharmacokinetic
properties).

Use in paediatrics
Durogesic 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 Durogesic transdermal
system administered.

Durogesic was not studied in children under 2 years of age. Durogesic

should be administered only to opioid-tolerant children age 2 years or older
(see Section 4.2). Durogesic 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 Durogesic (see Section 6.6) and monitor
adhesion of the patch closely.

Lactation

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 Final CSP for Fentanyl patches (Durogesic)
PSUR Worksharing Procedure

As fentanyl is excreted into breast milk, breastfeeding should be

discontinued during treatment with Durogesic (see also Section 4.6).

Patients with myasthenia gravis

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

Concomitant use of mixed agonists/antagonists

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

4.5 Interaction with other medicinal products and other forms

of interaction

The concomitant use of other central nervous system depressants, including

opioids, sedatives, hypnotics, general anesthetics, 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
Durogesic requires special patient care and observation.

Fentanyl, a high clearance drug, is rapidly and extensively metabolized

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 (See also Special
warnings and precautions for use, Section 4.4.).

Monoamine Oxidase Inhibitors (MAOI):

Durogesic 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,
Durogesic 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

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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 Pregnancy and lactation

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

Use of Durogesic during childbirth is not recommended because it should

not be used in the management of acute or postoperative pain (see
Section 4.4, Special warnings and precautions for use). Moreover, because
fentanyl passes through the placenta, the use of Durogesic 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 breastfed infant. Breastfeeding should therefore be
discontinued during treatment with Durogesic and for at least 72 hours after
removal of the patch.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The safety of Durogesic was evaluated in 1854 subjects who participated in

11 clinical trials (double-blind Durogesic [placebo or active control] and/or
open label Durogesic [no control or active control]) used for the
management of chronic malignant or non-malignant pain. These subjects
took at least 1 dose of Durogesic 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 Durogesic from these clinical trials,
including the above-mentioned ADRs, and from post-marketing experiences
are listed below.

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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).
Adverse Drug Reactions
System Organ Frequency Category
Class Very Common Common Uncommon Rare Not Known

Anaphylactic
shock,
Immune System Anaphylactic
Hypersensitivity
Disorders reaction,
Anaphylactoid
reaction
Metabolism and
Nutrition Anorexia
Disorders
Insomnia,
Depression,
Agitation,
Psychiatric Anxiety,
Disorientation,
Disorders Confusional
Euphoric mood
state,
Hallucination
Hypoaesthesia,
Convulsion
Somnolence, (including clonic
Nervous System Tremor,
Dizziness, convulsions and
Disorders Paraesthesia
Headache grand mal
convulsion),
Amnesia

Eye Disorders Miosis

Ear and
Labyrinth Vertigo
Disorders
Cardiac Palpitations, Bradycardia,
Disorders Tachycardia Cyanosis
Vascular
Hypertension Hypotension
Disorders
Respiratory, Respiratory
Thoracic and depression, Apnoea,
Dyspnoea Bradypnoea,
Mediastinal Respiratory Hypoventilation
Disorders distress
Diarrhoea, Dry
Nausea, mouth,
Gastrointestinal
Vomiting, Abdominal pain, Ileus Subileus
Disorders
Constipation Abdominal pain
upper, Dyspepsia

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Adverse Drug Reactions

System Organ Frequency Category
Class Very Common Common Uncommon Rare Not Known

Eczema,
Dermatitis
Skin and Hyperhidrosis, allergic, Skin
Subcutaneous Pruritus, Rash, disorder,
Tissue Disorders Erythema Dermatitis,
Dermatitis
contact
Musculoskeletal
and Connective Muscle spasms Muscle twitching
Tissue Disorders
Renal and
Urinary Urinary retention
Disorders
Reproductive Erectile
System and dysfunction,
Breast Sexual
Disorders dysfunction
Application site
reaction,
Influenza like
Fatigue, Oedema illness, Feeling
General Application site
peripheral, of body
Disorders and dermatitis,
Asthenia, temperature
Administration Application site
Malaise Feeling change,
Site Conditions eczema
cold Application site
hypersensitivity,
Drug withdrawal
syndrome

As with other opioid analgesics, tolerance, physical dependence, and

psychological dependence can develop on repeated use of Durogesic (see
Section 4.4, Special warnings and special precautions for use).

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety,

and shivering) are possible in some patients after conversion from their
previous opioid analgesic to Durogesic or if therapy is stopped suddenly (see
Section 4.2, Posology and method of administration). There have been very rare
reports of newborn infants experiencing neonatal withdrawal syndrome when
mothers chronically used Durogesic during pregnancy (see Section 4.6,
Pregnancy and lactation).

Paediatric Subjects
The adverse event profile in children and adolescents treated with
®
DUROGESIC 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 DUROGESIC use in children as young

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as 2 years old when used as directed. Very common adverse events reported in
paediatric clinical trials were fever, vomiting, and nausea.

4.9 Overdose

Symptoms
The manifestations of fentanyl overdosage are an extension of its
pharmacologic actions, the most serious effect being respiratory depression.

Treatment
For management of respiratory depression, immediate countermeasures
include removing the Durogesic 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.

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