Durogesic

Durogesic

fentanyl

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Fentanyl.
Description
Durogesic also contains the following excipients: Backing layer: Polyester/EVA; drug layer: Polyacrylate adhesive; protective line: Siliconized polyester; inks (on backing): Orange/red/green/blue/grey printing ink.
Durogesic is a novel, translucent, rectangular transdermal system with rounded corners. It is based on a simple drug-in-adhesive matrix design comprising of 2 active layers: A drug-in-adhesive layer and an occlusive backing layer, protected by an S-cut removable liner. From the outer surface to the surface adhering to skin, these layers are: Backing layer of polyester film; drug-in-adhesive layer (polyacrylate adhesive and fentanyl which in conjunction with the patient's strateum corneum, control the permeation of fentanyl across the skin) and S-cut slit protective liner (siliconised polyethylene terephthalate). Before use, a protective liner covering the adhesive layer is removed and discarded.
The 5.25-, 10.5- and 21-cm2 systems are designed to deliver 12, 25 and 50 mcg/hr fentanyl to the systemic circulation, respectively, which represent about 0.3, 0.6 and 1.2 mg/day, respectively.
Action
Pharmacology: Fentanyl is an opioid analgesic, interacting predominantly with the μ-opioid receptor. Its primary therapeutic actions are analgesia and sedation. Minimum effective analgesic serum concentrations of fentanyl in opioid-naive patients range from 0.3-1.5 ng/mL; side effects increase in frequency at serum levels above 2 ng/mL. Both the minimum effective concentration and the concentration at which toxicity occurs rise with increasing tolerance. The rate of development of tolerance varies widely among individuals.
Pharmacokinetics: Durogesic provides continuous systemic delivery of fentanyl during the 72-hr application period. Fentanyl is released at a relatively constant rate, determined by the copolymer release membrane and the diffusion of fentanyl through the skin layers. After initial Durogesic application, serum fentanyl concentrations increase gradually, generally leveling off between 12 and 24 hrs and remaining relatively constant for the remainder of the 72-hr application period. The serum fentanyl concentrations attained are proportional to the Durogesic patch size. After repeated 72-hr applications, patients reach a steady-state serum concentration that is maintained during subsequent applications of a patch of the same size.
After Durogesic is removed, serum fentanyl concentrations decline gradually, falling about 50% in about 17 (range 13-22) hrs following a 24-hr application. Following a 72-hr application, the mean terminal half-life ranges from 20-25 hrs. 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. Elderly, cachectic, or debilitated patients may have a reduced clearance of fentanyl and, therefore, the drug may have a prolonged terminal half-life in them. Adjusting for body weight, clearance in pediatric patients was about 20% higher than that in adults. These findings have been taken into consideration in determining the dosing recommendations for pediatric patients.
Fentanyl is a high clearance drug and is rapidly and extensively metabolized primarily by CYP3A4 in the liver. Around 75% of fentanyl is excreted into the urine, mostly as metabolites, with <10% as unchanged drug. About 9% of the dose is recovered in the feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13% and 21%.
Toxicology: 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. There are no long-term animal studies to investigate the tumor-forming potential of fentanyl.
Some tests on female rats showed reduced fertility as well as embryo mortality. These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo. There was no evidence of teratogenic effects.
Indications/Uses
Management of chronic pain and intractable pain that requires continuous opioid administration for an extended period of time.
Dosage/Direction for Use
Durogesic doses should be individualized based upon the status of the patient and should be assessed at regular intervals after application.
Initial Dose Selection: The size of the initial Durogesic dose should be based on the patient's opioid use. It is recommended that Durogesic 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, refer to Equianalgesic potency conversion (see Table 1) and recommended Durogesic daily dose based upon daily oral morphine dose (see Table 2). The dosage may be 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 depending on response and supplementary analgesic requirements.
Opioid-Naive Patients: Clinical experience with Durogesic is limited in opioid-naive patients. In the circumstance in which therapy with Durogesic is considered appropriate in opioid-naive patients, it is recommended that these patients be titrated with low doses of opioids to attain equianalgesic dose to Durogesic 25 mcg/hr. Patients can then be converted to Durogesic 25 mcg/hr. The dosage may subsequently by titrated upwards or downwards, if required, in increments of either 12 or 25 mcg/hr to achieve the lowest appropriate dose of Durogesic depending on response and supplementary analgesic requirements. (See Tables 1 and 2.) (See Precautions: Opioid-naive and Not Opioid-tolerant States.)
Children: Durogesic should be administered only to opioid-tolerant pediatric patients (2-16 years) who are already receiving at least 30 mg oral morphine equivalents per day. To convert pediatric patients from oral or parenteral opioids to Durogesic refer to Equianalgesic potency conversion (see Table 1) and Recommended Durogesic dose based upon daily oral morphine dose (see Table 2).
Clinical experience with Durogesic is limited in opioid-naive patients. In the circumstance in which therapy with Durogesic is considered appropriate in opioid-naive patients, it is recommended that these patients be titrated with low doses of opioids to attain equianalgesic dose to Durogesic dose, 25 mcg/hr.
Equianalgesic Potency Conversion: 1. Calculate the previous 24-hr 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.

Click on icon to see table/diagram/image

3. Table 2 displays the range of 24-hr oral morphine doses that are recommended for conversion to each Durogesic dose. Use this table to derive from the calculated 24-hr morphine dose the corresponding Durogesic dose.

Click on icon to see table/diagram/image

Initial evaluation of the maximum analgesic effect of Durogesic cannot be made before the patch is worn for 24 hrs. This delay is due to the gradual increase in serum fentanyl concentration in the 24 hrs following initial patch application.
Previous analgesic therapy should therefore be gradually phased out after the initial dose application until analgesic efficacy with Durogesic is attained.
Dose Titration and Maintenance Therapy: A 12 mcg/hr strength is available for dose titration. The Durogesic patch should be replaced every 72 hrs. The dose should be titrated individually until analgesic efficacy is attained. If analgesia is insufficient after the initial application the dose may be increased after 3 days. Thereafter, dose adjustment can take place every 3 days. Dosage titration should normally be performed in 12 mcg/hr or 25 mcg/hr increments, although the supplementary analgesic requirements (oral morphine 45/90 mg/day ~ Durogesic 12/25 mcg/hr) and pain status of the patient should be taken into account. More than one Durogesic patch may be used for doses greater than 100 mcg/hr. Patients may require periodic supplemental doses of a short-acting analgesic for "breakthrough" pain. Some patients may require additional or alternative methods of opioid administration when the Durogesic dose exceeds 300 mcg/hr.
Discontinuation of Durogesic: If discontinuation of Durogesic is necessary, 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 takes ≥17 hrs for the fentanyl serum concentration to decrease 50%. In general, the discontinuation of opioid analgesia should be gradual in order to prevent withdrawal symptoms.
Opioid withdrawal symptoms (see Adverse Reactions) are possible in some patients after conversion or dose adjustment.
Administration: Starting with Durogesic: Find an intact and hairless spot of skin on the upper part of the trunk or on the upper arm. There should be no tiny wounds nor may the skin be red, burnt or irradiated. Cut off any remaining hairs with a pair of scissors (do not shave them off since this will affect the skin). If the site of Durogesic application requires to be cleansed prior to application of the system, this should be done with clean water (no soap). The skin should be completely dry before the system is applied.
Open the package just before the application of Durogesic. Cut the pouch at the arrow from the side to the notch. Gently tear open the pouch along the side. Further open the pouch along both sides, folding the pouch open like a book.
Remove the patch.
Loosen the larger plastic cover by one of the corners and remove it entirely. Avoid touching the adhesive side of the patch.
Apply the patch to the skin and press it tightly with the palm of the hand for about 30 sec. Make sure the entire patch is in contact with the skin and especially that the corners are stuck tight.
Then wash the hands with clean water (no soap).
Durogesic may be worn continuously for 3 days (72 hrs). A new system should be applied to a different skin after removal of the previous transdermal system. Several days should elapse before a new patch is applied to the same area of the skin. The patient may have a bath, a shower or a swim.
Always note down on the packet the date when the patch is applied.
There is a space provided on the box. It will help on the correct use of Durogesic and to remember when the 3 days are over.
Changing a Patch of Durogesic: After 3 days, remove the patch by tearing it loose.
Immediately fold a used patch in half with the adhesive side facing inward and throw it away.
Apply a new patch right away, but never at the same place as the previous one. Pick another spot of intact skin.
Follow the instructions under Starting with Durogesic.
Overdosage
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 and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist eg, 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 system 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.
Contraindications
Known hypersensitivity to fentanyl or to the adhesives present in the system.
Special Precautions
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 hrs after Durogesic removal since serum fentanyl concentrations decline gradually and are reduced by about 50%, 17 (range 13-22) hrs later.
It is not possible to ensure the interchangeability of different makes of fentanyl transdermal patches in individual patients. Therefore, it should be emphasized that patients should not be changed from 1 make of fentanyl transdermal patches to another without specific counseling on the change from their healthcare professionals.
When converting a patient from 1 transdermal patch system containing fentanyl to another, additional medical supervision is recommended to ensure continuous pain relief and safety ie, a clinical evaluation and certainly a dose adjustment as with initial dose titration.
Durogesic should be kept out of reach of children before and after use.
Do not cut Durogesic patches.
Opioid-Naive and not Opioid-Tolerant States: Use of Durogesic transdermal system in the opioid-naive patient 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 transdermal system is used in initiating therapy in opioid-naive patients. It is recommended that Durogesic be used in patients who have demonstrated opioid tolerance. (See Dosage & Administration.)
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 system. 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: 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.
Drug Dependence and Potential for Abuse: Tolerance, physical and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is rare.
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. 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.
Increased Intracranial Pressure: Durogesic should be used with caution in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention eg, 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 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 should be reduced if necessary.
Fever/External Heat Application: A pharmacokinetic model suggests that serum fentanyl concentrations may increase by about 1/3 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. All patients should be advised to avoid exposing the Durogesic application site to direct external heat sources eg, heating pads, electric blankets, heated water beds, heat lamps, intensive sunbathing, hot water bottles, saunas and hot whirlpool spa baths.
Interactions with Other Medicaments: Interactions with CYP3A4 Inhibitors: The concomitant use of Durogesic with cytochrome P-450 3A4 (CYP3A4) inhibitors (eg, 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.
Effects on the Ability to Drive or Operate Machinery: Durogesic may impair mental and/or physical ability required for the performance of potentially hazardous tasks eg, driving a car or operating machinery.
Use in pregnancy & lactation: There are no adequate data from the use of Durogesic in pregnant women. Studies in animals have shown some reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is unknown. 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 fentanyl passes through the placenta and may cause respiratory depression in the newborn child.
Fentanyl is excreted into human milk and may cause sedation/respiratory depression in the newborn/infant. Therefore, Durogesic is not recommended for use in nursing women.
Use in children: Durogesic was not studied in children <2 years. Durogesic should be administered only to opioid-tolerant children age ≥2 years (see Dosage & Administration).
To guard against accidental ingestion by children, use caution when choosing the application site for Durogesic (see Cautions for Usage) and monitor adhesion of the patch closely.
Use in the elderly: Data from IV 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 studies of Durogesic, elderly patients had fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly patients should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
Use In Pregnancy & Lactation
There are no adequate data from the use of Durogesic in pregnant women. Studies in animals have shown some reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The potential risk for humans is unknown. 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 fentanyl passes through the placenta and may cause respiratory depression in the newborn child.
Fentanyl is excreted into human milk and may cause sedation/respiratory depression in the newborn/infant. Therefore, Durogesic is not recommended for use in nursing women.
Adverse Reactions
Clinical Trial Data: A multicenter, double-blind, randomized, placebo-controlled clinical study (FEN-EMA-1) of Durogesic examined patients (>40 years) with severe pain induced by osteoarthritis of the hip or knee and who were in need of and waiting for joint replacement. Patients were treated for 6 weeks with Durogesic by titrating to adequate pain control starting from 25 mcg/hr to a maximum dose of 100 mcg/hr in 25 mcg/hr increments. This treatment was preceded by a 1-week washout period and followed by a tapering-off period of no more than 12 days. The adverse events, regardless of causality, reported by ≥1% of the patients treated with Durogesic during the double-blind period and reported at a frequency greater than with placebo are presented in Table 3.

Click on icon to see table/diagram/image

The adverse event profile in children and adolescents treated with Durogesic was similar to that observed in adults. No risk was identified in the pediatric 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 pediatric-specific risk associated with Durogesic use in children as young as 2 years old when used as directed. Very common adverse events reported in pediatric clinical trials were fever, vomiting, and nausea.
Post-Marketing Data: Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience involving all indications with Durogesic that met threshold criteria are included in Table 4. The adverse drug reactions are ranked by frequency, using the following convention: Very common ≥1/10; common ≥1/100 and <1/10; uncommon ≥1/1000 and <1/100; rare ≥1/10,000 and <1/1000; very rare <1/10,000, including isolated reports.
The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates that might be obtained in clinical or epidemiological studies. (See Table 4.)

Click on icon to see table/diagram/image

As with other opioid analgesics, tolerance, physical dependence, and psychological dependence can develop on repeated use of Durogesic (see Precautions). Opioid withdrawal symptoms (eg, nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to Durogesic or if therapy is stopped suddenly (see Dosage & Administration). There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used Durogesic during pregnancy (see Use in pregnancy & lactation under Preacutions).
Drug Interactions
The concomitant use of other CNS depressants, including opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquilizers, 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 these drugs concomitantly with Durogesic requires special care and observation.
Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4.
The concomitant use of potent CYP3A4 inhibitors 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 CYP3A4 and transdermal fentanyl is not recommended, unless the patient is closely monitored (see Precautions).
Monoamine Oxidase Inhibitors (MAOI): Durogesic is not recommended for use in patients who require the concomitant administration of a MAOI. Severe and unpredictable interactions with MAIOs, involving the potentiation of opiate effects or the potentiation of serotoninergic effects, have been reported.
Caution For Usage
Instructions for Use/Handling: Durogesic should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arms. In young children, the upper back is the preferred location to minimize the potential of the child removing the patch. Hair at the application site (a nonhairy area is preferable) should be clipped (not shaved) prior to application. If the site of Durogesic application requires cleansing prior to application of the patch, this should be done with clear 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.
Durogesic should be applied immediately upon removal from the sealed package. To remove the patch from the protective pouch, locate the pre-cut notch (indicated by an arrow on the pouch label) along the edge of the seal. Fold the pouch at the notch, then carefully tear the pouch material. Further open the pouch along both sides, folding the pouch open like a book. The release liner for the matrix is slit. Fold the patch in the middle and remove each half of the liner separately. Avoid touching the adhesive side of the patch. Apply the patch to the skin by applying light pressure with the palm of the hand for about 30 sec. Make certain that the edges of the patch are adhering properly. Then wash with clean water.
Durogesic may be worn continuously for 72 hrs. A new patch should 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 the skin.
Used patches should be folded so that the adhesive side of the patch adheres to itself and then they should be safely discarded. Unused patches should be returned to the (hospital) pharmacy.
Wash hands, with water only, after applying or removing the patch.
Storage
Store in original container and not above 25°C.
MIMS Class
ATC Classification
N02AB03 - fentanyl ; Belongs to the class of phenylpiperidine derivative opioids. Used to relieve pain.
Presentation/Packing
Transdermal system 12 mcg/hr x 5's. 25 mcg/hr x 5's. 50 mcg/hr x 5's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in