Durogesic^® DTrans^® 12/25/50/75/100 mcg/hr Transdermal Patch

Each Durogesic DTrans 12/25/50/75/100 patch contains fentanyl 2.1/4.2/8.4/12.6/16.8 mg.

Release rate approximately 12/25/50/75/100 µg/h; active surface area 5.25/10.5/21.0/31.5/42.0 cm².

For excipients, see 6.1

Transdermal patch.

Each patch is marked:

Durogesic

12, 25, 50, 75 or 100 µg fentanyl/h

Orange/Red/Green/Blue/Grey printing ink

Adults:

Durogesic DTrans is indicated

- in the management of chronic intractable pain due to cancer

- in the management of chronic intractable pain

Children:

- long term management of severe chronic pain in children receiving opioid therapy from 2 years of age.

For transdermal use.

Durogesic DTrans should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arm. In young children, the upper back is the preferred location to apply the patch, to minimise the potential of the child removing the patch. A non-hairy area should be selected. If this is not possible, hair at the application site should be clipped (not shaved) prior to application. If the site of Durogesic DTrans application requires to be cleansed prior to application of the patch, this should be done with water. Soaps, oils, lotions or any other agent that might irritate the skin or alter its characteristics should not be used. The skin should be completely dry before the patch is applied. Patches should be inspected prior to use. Patches that are cut, divided, or damaged in any way should not be used.

The Durogesic DTrans patch should be removed from the protective pouch by first folding the notch (located close to the tip of the arrow on the pouch label) and then carefully tearing the pouch material. If scissors are used to open the pouch, this should be done close to the sealed edge so as not to damage the patch inside.

Durogesic DTrans should be applied immediately after removal from the sealed pouch. Avoid touching the adhesive side of the patch. Following removal of both parts of the protective liner, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges. Then wash hands with clean water.

Durogesic DTrans should be worn continuously for 72 hours. A new patch should then be applied to a different skin site after removal of the previous transdermal patch. Several days should elapse before a new patch is applied to the same area of skin.

The need for continued treatment should be assessed at regular intervals.

Initial dose selection

The appropriate initiating dose of Durogesic DTrans should be based on the patient's current opioid use. It is recommended that Durogesic DTrans 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 Durogesic DTrans 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 Durogesic DTrans depending on response and supplementary analgesic requirements.

Opioid-naive patients

In strong opioid-naive patients, the normal initial Durogesic DTrans dosage should not exceed 25 mcg/h.

Clinical experience with Durogesic DTrans is limited in opioid-naïve patients. In the circumstances in which therapy with Durogesic DTrans 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 Durogesic DTrans with a release rate of 25 mcg/hr. Patients can then be converted to Durogesic DTrans 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 Durogesic DTrans 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).

Equianalgesic potency conversion

1. Calculate the previous 24-hour analgesic requirement.

2. Convert this amount to the equianalgesic oral morphine dose using Table 1. All IM and oral doses in this chart are considered equivalent to 10 mg of IM morphine in analgesic effect.

3. To derive the dosage of Durogesic DTrans corresponding to the calculated 24-hour, equianalgesic morphine dosage, use the dosage-conversion Table 2 or Table 3 as follows:

Table 2 is for adult patients who have been stabilised on oral morphine or another immediate-release opioid over several weeks and who need opioid rotation (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 150:1).

Table 3 is for highly opioid-tolerant adult patients who have been on a stable and well-tolerated opioid regimen for a long period, and who need opioid rotation (conversion ratio of oral morphine to transdermal fentanyl approximately equal to 100:1).

Tables 2 and 3 should not be used to switch from transdermal fentanyl to another opioid treatment.

Table 1 Equianalgesic potency conversion

* Based on single-dose studies in which an IM dose of each drug listed was compared with morphine to establish the relative potency. Oral doses are those recommended when changing from a parenteral to an oral route.

** The oral/IM potency for morphine is based on clinical experience in patients with chronic pain.

Reference: Adapted from Foley KM. The treatment of cancer pain. NEJM 1985; 313 (2): 84-95, with updates.

Table 2: Recommended initial Durogesic DTrans dosage based upon daily oral morphine dosage¹ (for patients stabilised on oral morphine or immediate release opioid for several weeks and who need opioid rotation)

¹ In clinical trials these ranges of daily oral morphine dosages were used as a basis for conversion to Durogesic DTrans.

Table 3: Recommended initial Durogesic DTrans dosage based upon daily oral morphine dosage (for patients on stable and well tolerated opioid therapy for long periods and who need opioid rotation)

Previous analgesic therapy should be phased out gradually from the time of the first patch application until analgesic efficacy with Durogesic DTrans is attained. For both strong opioid-naïve and opioid tolerant patients, the initial evaluation of the analgesic effect of Durogesic DTrans should not be made until the patch has been worn for 24 hours due to the gradual increase in serum fentanyl concentrations up to this time.

Dose titration and maintenance therapy

The Durogesic DTrans patch should be replaced every 72 hours. The dose should be titrated individually until a balance between analgesic efficacy and tolerability is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of fentanyl after 48 hours may be necessary. If analgesia is insufficient at the end of the initial application period, the dose may be increased. Dose adjustment, when necessary, should normally be performed in the following titration steps from 25 mcg/hr up to 75 mcg/hr: 25 mcg/hr, 37 mcg/hr, 50 mcg/hr, 62 mcg/hr and 75 mcg/hr; thereafter dose adjustments should normally be performed in 25 mcg/hr increments, although the supplementary analgesic requirements (oral morphine 90 mg/day ≈ Durogesic DTrans 25 mcg/hr) and pain status of the patient should be taken into account. More than one Durogesic DTrans patch may be used to achieve the desired dose. Patients may require periodic supplemental doses of a short-acting analgesic for 'breakthrough' pain. Additional or alternative methods of analgesia should be considered when the Durogesic DTrans dose exceeds 300 mcg/hr.

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.

Opioid withdrawal symptoms (See section 4.8, Undesirable effects) are possible in some patients after conversion or dose adjustment.

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. 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).

Paediatric population

Children aged 16 years and above: follow adult dosage

Children aged 2 to 16 years old:

Durogesic DTrans should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day. To convert paediatric patients from oral opioids to Durogesic DTrans refer to Table 4, Recommended Durogesic DTrans dose based upon daily oral morphine dose.

Table 4: Recommended Durogesic DTrans dose based upon daily oral morphine dose¹

¹ In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to Durogesic DTrans

² Conversion to Durogesic DTrans doses greater than 25 mcg/hr is the same for adult and paediatric patients

For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 44 mg oral morphine per day or its equivalent opioid dose was replaced by one Durogesic DTrans 12 patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to Durogesic DTrans patches. The conversion schedule should not be used to convert from Durogesic DTrans into other opioids, as overdosing could then occur.

The analgesic effect of the first dose of Durogesic DTrans patches will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to Durogesic DTrans, 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 Durogesic DTrans therapy or up-titration of the dose (see also section 4.4, Special warnings and precautions for use).

Dose titration and maintenance

If the analgesic effect of Durogesic DTrans is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to increase the dose. Dose adjustments should be done in 12 mcg/hr steps.

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.

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)

It is not possible to ensure the interchangeability of different makes of fentanyl transdermal patches in individual patients. Therefore, it should be emphasised 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.

Durogesic DTrans should be kept out of reach and sight of children at all times before and after use.

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

Use of Durogesic DTrans in opioid-naïve patients has been associated with very rare cases of significant respiratory depression and/or fatality when used as initial opioid therapy. The potential for serious or life-threatening hypoventilation exists even if the lowest dose of Durogesic DTrans is used in initiating therapy in opioid-naïve patients. It is recommended that Durogesic DTrans be used in patients who have demonstrated opioid tolerance (See Section 4.2, Posology and method of administration).

When Durogesic DTrans is administered for chronic intractable pain that will require prolonged treatment, it is strongly recommended that the physician defines treatment outcomes with regards to pain relief and functional improvement in accordance with locally defined pain management guidelines. Physician and patient should agree to discontinue treatment if these objectives are not met.

Respiratory depression

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

Interactions with other Medicinal Products:

Interactions with CYP3A4 Inhibitors

The concomitant use of Durogesic DTrans with cytochrome P450 3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, erythromycin, 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 cytochrome P450 3A4 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, Interaction with other medicinal products and other forms of interaction).

Chronic pulmonary disease

Fentanyl, like other opioids, may have more severe adverse effects in patients with chronic obstructive or other pulmonary disease. In such patients, opioidsmay 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 such as fentanyl. 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 DTrans may result in overdose and/or death.

Increased intracranial pressure

Durogesic DTrans 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 DTrans should be used with caution in patients with brain tumours.

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.

Hepatic impairment

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

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 Cmax values by 61%.

All patients should be advised to avoid exposing the Durogesic DTrans 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.

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).

Use in paediatric patients

Durogesic DTrans should not be administered to opioid-naïve paediatric patients (see section 4.2, Posology and method of administration). The potential for serious or life-threatening hypoventilation exists regardless of the dose of Durogesic DTrans administered (see Table 2 in section 4.2, Posology and method of administration).

Durogesic DTrans has not been studied in children under 2 years of age and so should not be used in these children. Durogesic DTrans should be administered only to opioid-tolerant children age 2 years or older (see section 4.2, Posology and method of administration).

To guard against accidental ingestion by children, use caution when choosing the application site for Durogesic DTrans (see section 4.2, Posology and method of administration) and monitor adhesion of the patch closely.

Patch disposal

Used patches may contain significant residues of active substance. After removal, therefore, used patches should be folded firmly in half, adhesive side inwards, so that the adhesive is not exposed, and then discarded safely and out of the reach of children according to the instructions in the pack.

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.

The concomitant use of other Central Nervous System depressants, including opioids, sedatives, anxiolytics, hypnotics, general anaesthetics, phenothiazines, tranquilizers, 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 the above mentioned concomitant drugs requires special care and observation.

Fentanyl, a high clearance drug, is rapidly and extensively metabolised 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 Section 4.4, Special Warnings and Precautions for Use).

Monoamine Oxidase Inhibitors (MAOI)

Durogesic DTrans 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 DTrans 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 dependent patients (see also Section 4.4, Special Warnings and Precautions for Use).

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 in other formulations, fentanyl as an IV anaesthetic has been found to cross the placenta in early human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of 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). Moreover, because fentanyl passes through the placenta, the use of Durogesic DTrans 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 DTrans and for at least 72 hours after removal of the patch.

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

The safety of Durogesic was evaluated in 1854 adult and paediatric 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 one dose of Durogesic and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (ie 10% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), headache (11.8%) and insomnia (10.2%).

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 in Table A.

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).

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.

The safety of Durogesic was evaluated in 289 paediatric subjects (<18 years) who participated in 3 clinical trials for the management of chronic or continuous pain of malignant or non-malignant origin. These subjects took at least one dose of Durogesic and provided safety data. Although the enrolment criteria for the paediatric studies restricted enrolment to subjects who were a minimum of 2 years of age, 2 subjects in these studies received their first dose of Durogesic at an age of 23 months.

Based on pooled safety data from these 3 clinical trials in paediatric subjects, the most commonly reported (ie 10% incidence) Adverse Drug Reactions (ADRs) were (with % incidence): vomiting (33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%). Table B displays all ADRs reported in Durogesic-treated paediatric subjects in the aforementioned clinical trials.

The ADRs for the paediatric population presented in Table B were assigned to frequency categories using the same conventions as used for Table A.

As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can develop on repeated use of Durogesic DTrans (see Section 4.4, Special warnings and 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 DTrans or if therapy is stopped suddenly (see Section 4.2, Posology and method of administration).

There have been reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used Durogesic DTrans during pregnancy (see Section 4.6, Pregnancy and lactation).

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.

If severe or persistent hypotension occurs, hypovolaemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.

Pharmacotherapeutic group: opioids: phenylpiperidine derivatives

ATC code: N02A B03

Fentanyl is an opioid analgesic with a high affinity for the µ-opioid receptor.

Paediatric Patients

The safety of Durogesic DTrans was evaluated in three open-label trials in 289 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged to 2 to 6 years. In these studies, 30 mg to 44 mg oral morphine per day was replaced by one Durogesic 12 μg/h patch. Starting doses of 25 μg/h 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.

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 μg/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).

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.

Polyacrylate adhesive

Polyethylene terephthalate/ethyl vinyl acetate film

Orange/Red/Green/Blue/Grey printing ink

Siliconised polyester film

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

2 years.

This medicinal product does not require any special storage precautions.

Each patch is packed in a heat-sealed pouch made of polyethylene terephthalate (PET), low density polyethylene (LDPE), aluminium foil, adhesive and acrylonitrile film. Five pouches are assembled in a cardboard carton.

Please refer to section 4.2 for instructions on how to apply the patch. There are no safety and pharmacokinetic data available for other application sites.

After removal, the used patch should be folded in half, adhesive side inwards so that the adhesive is not exposed, placed in the original sachet and then discarded safely out of reach of children.

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

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PL 00242/0409; PL 00242/0192-5

POM/CD2