Change to section 5.3 - Preclinical Safety Data

In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation.  Fentanyl showed no evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays.

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumours at subcutaneous doses up to 33 µg/kg/day in males or 100 µg/kg/day in females.  The overall exposure (AUC_{0-24 h}) achieved in this study was <40% of that likely to be achieved clinically at the highest dose strength of Durogesic, 100 mcg/h, due to the maximum tolerated plasma concentrations in rats. 

Fentanyl was assessed for effects on fetal development in the rat and rabbit. Some tests on female rats showed reduced fertility as well as embryo mortality and transient development delays.  These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo.  These changes were observed at steady-state plasma concentrations equivalent to (C_ss, _rat / C_ss, _human = 1.1) and daily exposures slightly greater (AUC_{0-24, rat} / AUC_{0-24, human} = 1.5) than those observed in the clinic following use of the 100 mcg/h patch.  No effects were observed in the rabbit, where a maximum plasma concentration 6.6-fold the human steady-state fentanyl plasma concentration was achieved.  The daily exposure ratio (AUC_{4-24, rabbit} / AUC_{0-24, human} = 1.1) was equivalent to those observed in the clinic following use of the 100 mcg/h patch. There was no evidence of teratogenic effects.

Change to section 10 - Date of revision of the text

16 March 2011

Change to section 4.2 - Posology and method of administration

Discontinuation of Durogesic DTrans

If discontinuation of Durogesic DTrans is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly.  This is because fentanyl concentrations fall gradually after Durogesic DTrans is removed, it takes 17 hours or more for the fentanyl serum concentrations to decrease 50% (see Section 5.2, Pharmacokinetic Properties).  As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms.

Change to section 4.3 - Contraindications

Durogesic DTrans is contraindicated in patients with known hypersensitivity to fentanyl or to the excipients present in the patch.

Durogesic DTrans is a sustained-release preparation indicated for the treatment of chronic intractable pain and is contraindicated in acute or postoperative pain because of the lack of opportunity for dosage titration during short term use and the possibility of significant or life-threatening respiratory depression.

Change to section 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. (see section 5.2, Pharmacokinetic Properties)

………………

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). 

………….

Cardiac disease

Fentanyl may produce bradycardia and Durogesic DTrans 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. 

……

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 DTrans, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Section 5.2, Pharmacokinetic properties).

…..

Lactation

As fentanyl is excreted into breast milk, breastfeeding should be discontinued during treatment with Durogesic (see also Section 4.6, Pregnancy and lactation).

Patients with myasthenia gravis

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

Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

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, Special Warnings and Precautions for Use). 

Change to section 4.6 - Pregnancy and Lactation

Breastfeeding should therefore be discontinued during treatment with   Durogesic DTrans and for at least 72 hours after removal of the patch.

Change to section 4.7 - Effects on Ability to Drive and Use Machines

Minor changes

Change to section 4.8 - Undesirable Effects

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

Change to section 4.9 - Overdose

Minor changes

Change to section 10 - Date of revision of the text

15 March 2011

Change to section 4.2 - Posology and method of administration

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 Durogesic DTrans 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 section 5.2 Pharmacokinetic properties).

Change to section 4.4 - Special warnings and precautions for Use

Patients who have experienced serious adverse events should be monitored for up to 24 hours after Durogesic DTrans removal since serum fentanyl concentrations decline gradually with mean half-life ranging from 20-27 hours.

Change to section 5.2 - Pharmacokinetic Properties

Adults

Durogesic DTrans provides continuous systemic delivery of fentanyl over the 72 hour administration period.  Fentanyl is released at a relatively constant rate.  The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release.  After the first Durogesic DTrans application, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours, and remaining relatively constant for the remainder of the 72-hour application period.  The serum fentanyl concentrations attained are proportional to the Durogesic DTrans patch size.  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.

A pharmacokinetic model has suggested that serum fentanyl concentrations may increase by 14% (range 0- 26%) if a new patch is applied after 24 hours rather than the recommended 72-hour application.

Distribution

The plasma-protein binding of fentanyl is about 84%.

Metabolism

Fentanyl is a high clearance drug and is rapidly and extensively metabolised primarily by CYP3A4 in the liver.  The major metabolite, norfentanyl, is inactive.  Skin does not appear to metabolise fentanyl delivered transdermally.  This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.

Elimination

After Durogesic DTrans is removed, serum fentanyl concentrations decline gradually, falling about 50% in about 17 (range 13‑22) hours following a 24‑hour application.  Following a 72-hour application, the  mean half-life ranges from 20-27 hours.  Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3-12 hours)..  Fentanyl is metabolised primarily in the liver.  Within 72 hours of IV fentanyl administration, approximately 75% of the fentanyl dose is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug.  About 9% of the dose is recovered in the faeces, primarily as metabolites.  Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

Special populations

Elderly

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.  In a study conducted with Durogesic DTrans, healthy elderly subjects had fentanyl pharmacokinetics which did not differ significantly from healthy young subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.  Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.2 Posology and method of administration).

Paediatric Patients

Adjusting for body weight, clearance (L/hr/Kg) in paediatric patients appears to be 82% higher in children 2 to 5 years old and 25% higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are likely to have the same clearance as adults.  These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.

Hepatic impairment

In a study conducted with patients with hepatic cirrhosis, the pharmacokinetics of a single 50 mg/hr application of Durogesic DTrans were assessed.  Although t_max and t_1/2 were not altered, the mean plasma C_max and AUC values increased by approximately 35% and 73%, respectively, in these patients.  Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of Durogesic DTrans reduced if necessary (see section 4.4 Special warnings and precautions for use).

Renal impairment

Data obtained from a study administering IV fentanyl in patients undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population.  If patients with renal impairment receive Durogesic DTrans, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.4 Special warnings and precautions for use).

Change to section 10 - Date of revision of the text

11 February 2011

Change to section 4.6 – Pregnancy and Lactation

The safety of fentanyl in pregnancy has not been

established. Studies in animals have shown some

reproductive toxicity. The potential risk for humans is

unknown, although in other formulations,

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 DTrans during pregnancy. Durogesic DTrans should not be used during pregnancy unless clearly necessary.

Use of Durogesic DTrans during childbirth is not

recommended because it should not be used in the

management of acute pain (see section 4.3

Contraindications). Moreover, because fentanyl

passes through the placenta, the use of Durogesic

DTrans during childbirth might result in and may

cause respiratory depression in the newborn infant child.

Fentanyl is excreted into breast milk and may cause

sedation/respiratory depression in the newbornan

infant, hence. Therefore, Durogesic DTrans should not be used is not recommended for use by women who are breast-feeding.

Change to section 10 – Date of revision of the text

27 April 2010

Change to section 6.6 –  Instructions for use, handling and disposal

Wash hands with water only after applying or removing the patch.

Change to section 10 – Date of revision of the text

16 March 2010

Change to section 4.4 Special warnings and precautions for use

Addition of information on potential for abuse.

Addition of information on external heat sources (heated water beds, tanning lamps, intensive sun bathing, prolonged hot baths).

Change to section 10 Date of Revision of the Text

Amended to ’17 August 2009’

Change to section 4.6 Pregnancy and lactation

Addition of information on neonatal withdrawal syndrome

Change to section 4.8 Undesirable effects

Addition of information on neonatal withdrawal syndrome

Change to section 10 Date of Revision of the Text

Amended to ’31 July 2009’

Change to section 6.6 Special Precautions for Disposal

Amendment of sub-heading from ‘Instruction for use, handling and disposal’ to ‘Special Precautions for Disposal’

Change to section 9 Date of Renewal of the Authorisations

Amended to ‘3 March 2009’

Change to section 10 Date of Revision of the Text

Amended to ‘3 March 2009’

Change

eMC - Summary of Change Details Per Section

Change to section 4.2 – Posology and |Method of Administration

Addition of the following information to the existing text:

‘If this is not possible, hair at the application site should be clipped (not shaved) prior to application.’

‘Patches should be inspected prior to use.  Patches that are cut, divided, or damaged in any way should not be used.’

‘Avoid touching the adhesive side of the patch.’

‘Then wash hands with clean water.’

Change to section 7 – Marketing Authorisation Holder

Change of address

Change to section 10 – Date of revision of the text

10 September 2008

REASON(S) FOR SUBMISSION

Change

eMC - Summary of Change Details Per Section

Change to section 4.2 – Posology and |Method of Administration

Details added regarding

- initial dose selection

- opioid-naïve patients

- opioid withdrawal symptoms

Change to section 4.4 – Special Warnings and Precautions for Use

Details added regarding

- opioid-naïve patients and respiratory depression

- interactions with CYP3A4 inhibitors

Change to section 4.5 –Interaction with other medicinal products and other forms of interaction

Details added for

- CNS depressants

- CYP3A4 inhibitors

- MAOIs

Change to section 4.8 – Undesirable effects

Adverse events added from clinical trials and post-marketing experience.

Change to section 10 – Date of revision of the text

22 November 2007

Change to section 4.2 – Posology and Method of Administration

Addition of text regarding use in paediatric patients.

Change to section 4.4 – Special Warnings and Precautions for Use

Addition of text regarding use in paediatric patients.

Change to section 4.8 – Undesirable effects

Addition of information regarding paediatric patients.

Change to section 5.1 - Pharmacodynamic properties

Addition of text regarding use in paediatric patients.

Change to section 5.2 - Pharmacokinetic properties

Addition of text regarding use in paediatric patients.

Change to section 6.6 – Instructions for use, handling and disposal

Addition of text that data not available for other application sites.

Change to section 10 – Date of revision of the text

23 July 2007

REASON(S) FOR SUBMISSION

Change

eMC - Summary of Change Details Per Section

Change to section 4.4 – Special Warnings and Precautions for Use

Addition of text advising that patients should not be changed from one make of fentanyl transdermal patches to another without specific counselling on the change from their healthcare professionals.

Change to section 10 – Date of revision of the text

6 March 2007

SUMMARY OF PRODUCT CHARACTERISTICS – eMC Website

Company Name

Janssen-Cilag Ltd

Product Name(s)

Durogesic DTrans

Generic Name

Fentanyl

Legal Category

POM / CD2

Document contains Black Triangle?

No

Date of Revision of Text on SPC

1 March 2007

Date of Approval Letter

1 March 2007

Date Approval Letter received

5 March 2007

REASON(S) FOR SUBMISSION

Change

eMC - Summary of Change Details Per Section

Change to section 4.6 – Pregnancy and Lactation

Further details added regarding pregnancy and breastfeeding.    Text also added advising that Durogesic DTrans is not recommended for use during childbirth.

Change to section 10 – Date of revision of the text

1 March 2007

4.2 Posology and method of administration

Text deleted

In strong opioid-naive patients, the lowest Durogesic DTrans dose 25 mg/h, should be used as the initial dose.

Replaced with

In strong opioid-naive patients, Durogesic DTrans dose 25 mg/h, should be used as the initial dose.

10. DATE OF (PARTIAL) REVISION OF THE TEXT

18 July 2006