Durogesic DTrans 12 micrograms/hour Transdermal Patch

Change due to harmonisation of Summary of Product Characteristics in Europe (implementation of the outcome of a referral procedure under Article 30 of Directive 2001/83/EC).

Change due to harmonisation of Summary of Product Characteristics in Europe (implementation of the outcome of a referral procedure under Article 30 of Directive 2001/83/EC).

• Section 3 -  Transdermal patch. A rectangular shaped, clear patch with a sticky back so that it can be stuck onto the skin.

Each Durogesic DTrans patch is marked:

       Durogesic

       12, 25, 50, 75 or 100 µg fentanyl/h

• Section 3 -  Transdermal patch. A rectangular shaped, clear patch with a sticky back so that it can be stuck onto the skin.

Each Durogesic DTrans patch is marked:

       Durogesic

       12, 25, 50, 75 or 100 µg fentanyl/h

Durogesic DTrans is a sustained-release preparation indicated for the treatment of chronic intractable pain in patients requiring opioid analgesia and is contraindicated in acute or postoperative pain because of the lack of opportunity for dosage titration in the short term and the resultant possibility of serious or life threatening respiratory depression.

Change to section 4.4-  

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)

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.

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

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 intensive 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 DTrans may result in overdose and/or death. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations, however, these patients will require intensive monitoring for signs of misuse, abuse or addiction.

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

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 Durogesic DTrans 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 Durogesic DTrans transdermal system increased mean fentanyl AUC values by 120% and mean C_max values by 61%.

Patients who develop fever should be monitored for opioid side effects since significant increases in body temperature can potentially increase fentanyl delivery rate.

Interactions with other Medicinal Products:

Interactions with CYP3A4 inhibitors

The concomitant use of Durogesic DTrans 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 DTrans 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). 

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).

Lactation

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. 

Change to section 4.5- The concomitant use of other CNS depressants, including opioids, sedatives, anxiolytics, hypnotics, general anaesthetics, phenothiazines, tranquilisers, antipsychotics, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce additive depressant effects; hypoventilation, hypotension and profound sedation, coma or death may occur.  Therefore, the use of any of these drugs concomitantly with Durogesic DTrans requires special care and observation.

Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of IV fentanyl.  Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of IV fentanyl by two thirds.

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 for an extended period of time and dosage adjustments made if warranted (See also 4.4 Special Warnings and Precautions for Use).

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).

Change to section 4.6- 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 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 or postoperative pain (see section 4.3 Contraindications and 4.4, Special Warning and Precautions).

Change to section 4.7-Durogesic DTrans may impair the mental and/or physical ability required to perform potentially hazardous tasks such as driving a car or operating machinery.

Change to section 4.8-Addition of paediatric wording and updated paediatric table

Change to section 4.9-

Symptoms:

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

Treatment:

For management of respiratory depression, immediate countermeasures include removing Durogesic DTrans 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

Change to section 5.2-

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. 

Durogesic DTrans is a sustained-release preparation indicated for the treatment of chronic intractable pain in patients requiring opioid analgesia and is contraindicated in acute or postoperative pain because of the lack of opportunity for dosage titration in the short term and the resultant possibility of serious or life threatening respiratory depression.

Change to section 4.4-  

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)

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.

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

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 intensive 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 DTrans may result in overdose and/or death. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations, however, these patients will require intensive monitoring for signs of misuse, abuse or addiction.

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

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 Durogesic DTrans 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 Durogesic DTrans transdermal system increased mean fentanyl AUC values by 120% and mean C_max values by 61%.

Patients who develop fever should be monitored for opioid side effects since significant increases in body temperature can potentially increase fentanyl delivery rate.

Interactions with other Medicinal Products:

Interactions with CYP3A4 inhibitors

The concomitant use of Durogesic DTrans 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 DTrans 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). 

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).

Lactation

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. 

Change to section 4.5- The concomitant use of other CNS depressants, including opioids, sedatives, anxiolytics, hypnotics, general anaesthetics, phenothiazines, tranquilisers, antipsychotics, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce additive depressant effects; hypoventilation, hypotension and profound sedation, coma or death may occur.  Therefore, the use of any of these drugs concomitantly with Durogesic DTrans requires special care and observation.

Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of IV fentanyl.  Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of IV fentanyl by two thirds.

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 for an extended period of time and dosage adjustments made if warranted (See also 4.4 Special Warnings and Precautions for Use).

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).

Change to section 4.6- 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 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 or postoperative pain (see section 4.3 Contraindications and 4.4, Special Warning and Precautions).

Change to section 4.7-Durogesic DTrans may impair the mental and/or physical ability required to perform potentially hazardous tasks such as driving a car or operating machinery.

Change to section 4.8-Addition of paediatric wording and updated paediatric table

Change to section 4.9-

Symptoms:

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

Treatment:

For management of respiratory depression, immediate countermeasures include removing Durogesic DTrans 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

Change to section 5.2-

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.