Janssen Products

Fentanyl

Durogesic^TM

Description
Fentanyl (Durogesic^TM) is a transdermal system providing continuous systemic delivery of fentanyl, a potent opioid analgesic, for 72 hours.

Fentanyl (Durogesic^TM) is a rectangular transparent unit comprising a protective liner and four functional layers. From the outer surface to the surface adhering to skin, these layers are: 1) a backing layer of polyester film (ethylenevenyl acetate copolymer); 2) a drug reservoir of fentanyl (2.5 mg/10 cm²) and alcohol USP (0.1 mL/10 cm²) gelled with hydroxyethyl cellulose; 3) an ethylene-vinyl acetate copolymer membrane that controls the rate of fentanyl delivery; and 4) a layer of silicone adhesive. Before use, a protective liner covering the adhesive layer is removed and discarded.

Fentanyl (Durogesic^TM) is available in two different strengths, the composition of which per unit area is identical.

The 10- and 20-cm² systems are designed to deliver 25 and 50 µg/h fentanyl to the systemic circulation, which represent about 0.6 and 1.2 mg per day. The other components are pharmacologically inactive. Less than 0.2 ml of alcohol is released from the system during a 72-hour use.

Properties
Pharmacodynamics
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 to 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
Fentanyl (Durogesic^TM) provides continuous systemic delivery of fentanyl during the 72-hour 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 fentanyl (Durogesic^TM) application, serum fentanyl concentrations increase gradually, generally leveling 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 fentanyl (Durogesic^TM) patch size. After repeated 72-hour applications, patients reach a steady state serum concentration that is maintained during subsequent applications of a patch of the same size.

After fentanyl (Durogesic^TM) is removed, serum fentanyl concentrations decline gradually, falling about 50% in about 17 (range 13-22) 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. 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. Fentanyl is metabolized 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 feces, primarily as metabolites. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

Indications
Fentanyl (Durogesic^TM) is indicated in the management of chronic pain and intractable pain requiring opioid analgesia.

Contraindications
Fentanyl (Durogesic^TM) is contraindicated in patients with known hypersensitivity to fentanyl or to the adhesives present in the system.

Warnings and Precautions
Fentanyl (Durogesic^TM) 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 fentanyl (Durogesic^TM) removal since serum fentanyl concentrations decline gradually and are reduced by about 50%, 17 (range 13-22) hours later.

Fentanyl (Durogesic^TM) should be kept out of reach of children before and after use.

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

Respiratory Depression
As with all potent opioids, some patients may experience significant respiratory depression with fentanyl (Durogesic^TM); patients must be observed for these effects. Respiratory depression may persist beyond the removal of the fentanyl (Durogesic^TM) system. The incidence of respiratory depression increases as the fentanyl (Durogesic^TM) dose is increased. See also Overdosage concerning respiratory depression. CNS active drugs may increase the respiratory depression (see Interactions).

Chronic Pulmonary Disease
Fentanyl (Durogesic^TM) 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
Tolerance and physical and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is rare.

Increased Intracranial Pressure
Fentanyl (Durogesic^TM) 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. Fentanyl (Durogesic^TM) should be used with caution in patients with brain tumors.

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

Hepatic Disease
Because fentanyl is metabolized to inactive metabolites in the liver, hepatic disease might delay its elimination. In patients with hepatic cirrhosis, the pharmacokinetics of a single application of fentanyl (Durogesic^TM) 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 fentanyl (Durogesic^TM) 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 fentanyl (Durogesic^TM), they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.

Fever/External Heat Application
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 fentanyl (Durogesic^TM) dose should be adjusted if necessary. All patients should be advised to avoid exposing the fentanyl (Durogesic^TM) application site to direct external heat sources such as heating pads, electric blankets, heated water beds, heat lamps, intensive sunbathing, hot water bottles, saunas and hot whirlpool spa baths.

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. In studies of fentanyl (Durogesic^TM), 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 Children
The safety and efficacy of fentanyl (Durogesic^TM) in children has not been established.

Interactions
The concomitant use of other central nervous system depressants, including opioids, sedatives, hypnotics, general anesthetics, 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 fentanyl (Durogesic^TM) requires special patient care and observation.

Fentanyl, a high clearance drug, is rapidly and extensively metabolized mainly by CYP3A4.

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 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.
Pregnancy and Lactation
The safe use of fentanyl has not been established with respect to possible adverse effects upon fetal development. Therefore, fentanyl (Durogesic^TM) should not be used in women of childbearing potential unless, in the judgement of the physician, the potential benefits outweigh the possible hazards.

Fentanyl is excreted into human milk. Therefore fentanyl (Durogesic^TM) is not recommended for use in nursing women.

Effects on Driving Ability and Use of Machinery
Fentanyl (Durogesic^TM) may impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

Dosage and Administration
Fentanyl (Durogesic^TM) 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 fentanyl (Durogesic^TM) dose should be based on the patient's opioid history, including the degree of opioid tolerance, if any, as well as on the current general condition and medical status of the patient.

In opioid-naive patients, the lowest fentanyl (Durogesic^TM) dose, 25 µg/h, should be used as the initial dose.

In opioid-tolerant patients: to convert from oral or parenteral opioids to fentanyl (Durogesic), the following procedure should be followed:

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. Table 2 displays the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl (Durogesic^TM) dose. Use this table to derive from the calculated 24-hour morphine dose the corresponding fentanyl (Durogesic^TM) dose.

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 ratio of 1:3 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.

Table 2: Recommended fentanyl (Durogesic^TM) dose based upon daily oral morphine dose*

 *   In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to fentanyl (Durogesic^TM).

Both in opioid-naive and opioid-tolerant patients, the initial evaluation of the maximum analgesic effect of fentanyl (Durogesic^TM) cannot be made before the system is worn for 24 hours. This delay is due to the gradual increase in serum fentanyl concentration in the 24 hours following initial system application.

Previous analgesic therapy should therefore be gradually phased out after the initial dose application until analgesic efficacy with fentanyl (Durogesic^TM) is attained.

Dose Titration and Maintenance Therapy
The fentanyl (Durogesic^TM) patch should be replaced every 72 hours. 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 25 µg/h increments, although the supplementary analgesic requirements (oral morphine 90 mg/day ~ Durogesic^TM 25 µg/h) and pain status of the patient should be taken into account. More than one fentanyl (Durogesic^TM) system may be used for doses greater than 100 µg/h. 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 fentanyl (Durogesic^TM) dose exceeds 300 µg/h.

Discontinuation of Fentanyl (Durogesic^TM)
If discontinuation of fentanyl (Durogesic^TM) 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 fentanyl (Durogesic^TM) is removed, it takes 17 hours or more for the fentanyl serum concentration to decrease 50%. In general, the discontinuation of opioid analgesia should be gradual in order to prevent withdrawal symptoms.

Adverse Reactions
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, diarrhea, anxiety and shivering) are possible in some patients after conversion from their previous opioid analgesic to fentanyl (Durogesic^TM).

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 fentanyl (Durogesic^TM) 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 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.

Instructions for Use/Handling
Fentanyl (Durogesic^TM) should be applied to non-irritated and non-irradiated skin on a flat surface of the torso or upper arms. Hair at the application site (a non-hairy area is preferable) should be clipped (not shaved) prior to application. If the site of fentanyl (Durogesic^TM) application requires to be cleansed prior to application of the system, 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 system is applied.

Fentanyl (Durogesic^TM) should be applied immediately upon removal from the sealed package. The transdermal system 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.

Fentanyl (Durogesic^TM) may be worn continuously for 72 hours. A new system should be applied to a different skin site after removal of the previous transdermal system. Several days should elapse before a new patch is applied to the same area of the skin.

Used systems should be folded so that the adhesive side of the system adheres to itself and then they should be safely discarded. Unused systems should be returned to the (hospital) pharmacy. Disposal of the Patch
Used systems should be folded so that the adhesive side of the system adheres to itself, and then they should be discarded. Unused systems should be returned to the (hospital) pharmacy.

How Supplied
Fentanyl (Durogesic^TM) is available in two different strengths.

Fentanyl (Durogesic^TM) is supplied in cartons containing 5 individually packaged systems.

Storage Conditions
Store in sealed pouch between 15 and 25°C.
Keep out of reach of children.

Caution: Food, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription. (List A).

Manufactured by:
ALZA CORPORATION
Palo Alto, California, USA
Packed by:
INTERPHIL LABORATORIES, INC.
Canlubang Industrial Estate
Bo. Pittland, Cabuyao, Laguna
for: Johnson & Johnson (Philippines), Inc.
Edison Road, Bo. Ibayo
Parañaque, Metro Manila
Exclusively distributed by:
ZUELLIG PHARMA CORPORATION
Sen. Gil Puyat Avenue
Makati City