Oral 24-Hour Morphine (mg/day)	Durogesic (µg/h)
<135	25
135 - 224	50
225 - 314	75
315 - 404	100
405 - 494	125
495 - 584	150
585 - 674	175
675 - 764	200
765 - 854	225
855 - 944	250
945 - 1034	275
1035 - 1124	300

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

Dose titration and maintenance therapy
The Durogesic patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained.
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 25 ¦Ìg/h increments, although the supplementary analgesic requirements (oral morphine 90 mg/day ¡Ö Durogesic 25 ¦Ìg/h) and pain status of the patient should be taken into account.
More than one Durogesic patch may be used for doses greater than 100 ¦Ìg/h. 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 dose exceeds 300 ¦Ìg/h.

Discontinuation of Durogesic
If discontinuation of Durogesic 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 Durogesic is removed; it may take 17 hours or more 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.

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 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.

Use in Children
The safety and efficacy of Durogesic in children has not been established and is therefore not recommended.

Durogesic is contra-indicated in patients with known hypersensitivity to fentanyl or to the adhesive in the patch.

Durogesic is a sustained-release preparation indicated for the treatment of chronic intractable pain and is contra-indicated in acute pain because of the lack of opportunity for dosage titration in the short term and the resultant possibility of significant respiratory depression.

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% in approximately 17 (range 13-22) hours.

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

Durogesic patches should not be divided, cut or damaged in any other way since this leads to uncontrolled release of fentanyl.

When Durogesic 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; 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 also ¡®overdosage¡¯ concerning respiratory depression.

CNS active drugs may increase the respiratory depression (see ¡®interactions¡¯).

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, they may decrease respiratory drive and increase airway resistance.

Drug dependence

Tolerance and physical and psychological dependence may develop upon repeated administration of opioids such as fentanyl. Iatrogenic addiction following opioid administration is rare.

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 tumours.

Cardiac disease

Fentanyl may produce bradycardia and Durogesic should therefore be administered with caution to patients with bradyarrhythmias.

Hepatic disease

Because fentanyl is metabolised to inactive metabolites in the liver, hepatic disease might delay its elimination. In patients with hepatic cirrhosis, the pharmacokinetics of a single application of Durogesic were not altered although serum concentrations tended to be higher in these patients. Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity and the dose of Durogesic reduced if necessary.

Renal disease

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 Durogesic, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Patients with fever/external heat

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

Patients should also be advised to avoid exposing the Durogesic application site to direct external heat sources such as heating pads, hot water bottles, electric blankets, heat lamps, 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.

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 release membrane is not exposed, and then discarded safely and out of the reach of children according to the instructions in the pack.

The concomitant use of other CNS depressants, including opioids, anxiolytics, hypnotics, general anaesthetics, antipsychotics, skeletal muscle relaxants, sedating antihistamines and alcoholic beverages may produce additive depressant effects; hypoventilation, hypotension and profound sedation or coma 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.

Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for four 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 potent CYP3A4 inhibitors such as ritonavir with transdermal fentanyl 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 ritonavir and transdermal fentanyl is not recommended, unless the patient is closely monitored.

The safety of fentanyl in pregnancy has not been established. Durogesic should not be used in women of child-bearing potential without adequate contraception unless in the judgement of the doctor the potential benefits outweigh the possible hazards.

Fentanyl is excreted into breast milk hence Durogesic should not be used by women who are breast feeding.

Durogesic may impair the mental or physical ability required to perform

potentially hazardous tasks such as driving or operating machinery.

The most serious adverse reaction, as with all potent opioids, is hypoventilation.

Other opioid-related adverse reactions include: nausea; vomiting; constipation; hypotension; bradycardia; somnolence; headache; confusion; hallucinations; euphoria; pruritus; sweating and urinary retention.

Skin reactions such as rash, erythema and itching have occasionally been reported. These reactions usually resolve within 24 hours of removal of the patch.

Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety and shivering) are possible in some patients after conversion from their previous analgesic to Durogesic.

Symptoms
The symptoms 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 and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone. The interval between IV antagonist doses should be carefully chosen and repeated administration or a continuous infusion of naloxone may be necessary because of continued absorption of fentanyl from the skin after patch removal, which may result in prolonged respiratory depression. Reversal of the narcotic effect may result in acute onset of pain and release of catecholamines.

A patent airway should be established and maintained. 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.

Durogesic provides continuous systemic delivery of fentanyl over the 72 hour administration period. After the first Durogesic 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 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.

After Durogesic is removed, serum fentanyl concentrations decline gradually, falling approximately 50% in 17 (range 13-22) hours. Continued absorption f fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion. Fentanyl is metabolised primarily in the liver. Around 75% of fentanyl 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.

The major metabolite, norfentanyl, is inactive. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.