Contents

Fentanyl

Indication

This is used for the management of chronic pain and intractable pain requiring opioid analgesia particularly cancer pain.

Dosage / Direction For Use

Fentanyl doses should be individualized based upon the status of the patient and should be assessed at regular intervals after application. The patches are designed to deliver approximately 12, 25, 50, 75 and 100 mcg/hr fentanyl to the systemic circulation, which represent about 0.3, 0.6, and 1.2, 1.8 and 2.4 mg per day, respectively.Initial Dosage Selection: The appropriate initial dose of fentanyl should be based on the patient’s current opioid use. It is recommended that Fentanyl 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 fentanyl refer to Equianalgesic potency conversion as follows. 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 the depending on response and supplementary analgesic requirements.Opioid-Naïve Patients: Clinical experience with Fentanyl is limited in opioid-naïve patients. In the circumstances in which therapy with fentanyl 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 fentanyl with a release rate of 25 mcg/hr. (See table.)Click on icon to see table/diagram/imageChildren: Fentanyl should be administered to only those opioid-tolerant pediatric patients 2-16 yrs who are already receiving at least 30 mg oral morphine equivalents per day.Administration: Patients receiving transdermal fentanyl should be carefully instructed in the proper use and disposal of the transdermal system. To expose the adhesive surface of the system, the protective-liner covering should be peeled and discarded just prior to application. The transdermal system is applied to a dry, non-irritated flat surface on the upper torso by firmly pressing the system by hand for 30 seconds with the adhesive side touching the skin of the torso and ensuring that contact is complete, particularly around the edges. 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 (preferably non-hairy area) should be clipped (not shaved) prior to application. If transdermal therapy is discontinued for longer than 72 hours, a new transdermal system should be placed at a different site on the upper torso.

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 patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist e.g., naloxone. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. The interval between the 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 must be 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 IV fluid therapy.

Administration

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Contraindication

Because the absorption of topically applied fentanyl from the transdermal systems depends in part on the temperature of the skin, increasing with increased temperature, patients who develop a fever while using the transdermal system should be observed closely for manifestations of opiate toxicity, and dosage of the drug should be adjusted accordingly. In addition, patients wearing a transdermal system of the drug should be advised to avoid exposing the application site to direct external heat sources.

Special Precaution

Fentanyl should not be used in the management of acute or post-operative 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 experience serious adverse reactions should be monitored for up to 24 hrs after fentanyl removal since serum fentanyl concentrations decline gradually and are reduced by about 50% 17 (range 13-22) hrs later.Do not cut Sublimax patches. A patch that has been divided, cut, or damaged in any way should not be used.Opioid-Naïve and not Opioid-Tolerant States: Use of fentanyl transdermal system in the opioid naïve patient has been associated with every rare cases of significant respiratory depression and/or fatality when used as initial opioid therapy. The potential for a serious or life-threatening hypoventilation exists even if the lowest dose of fentanyl transdermal system is used in initiating therapy in opioid naïve patients. It is recommended that fentanyl transdermal patch be used in patients who have demonstrated opioid tolerance. Respiratory Depression: As with all potent opioids, some patients may experience significant respiratory depression with fentanyl; patients must be observed for these effects. Respiratory depression may persist beyond the removal of fentanyl patch. The incidence of respiratory depression increases as the fentanyl dose is increased (see Overdosage). Central nervous system (CNS) active drugs may increase the respiratory depression (see Interactions).Chronic Pulmonary Disease: Fentanyl may have more severe adverse reactions 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 dependence 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 fentanyl 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: Fentanyl should be used with caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention, e.g., those with evidence of increased intracranial pressure, impaired consciousness, or coma. It 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 Impairment: Because fentanyl is metabolized to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive fentanyl transdermal patch, they should be observed carefully for signs of fentanyl toxicity and the dose should be reduced if necessary.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 fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see Pharmacology: Pharmacokinetics under Actions).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 fentanyl 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 fentanyl system increased mean fentanyl AUC values by 120% and mean Cmax values by 61%. All patients should be advised to avoid exposing the fentanyl application site to direct external heat sources e.g. Heating pads, electric blankets, heated water beds, heat or tanning lamps, intensive sunbathing, hot water bottles, prolonged hot baths, saunas and hot whirlpool spa baths.Effects on the Ability to Drive or Operate Machinery: Fentanyl 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 and Lactation: There are no adequate data from the use of Fentanyl in pregnant women. Studies in animals have shown some reproductive toxicity. The potential risk for humans is unknown, although fentanyl is an IV anesthetic has been found to cross the placenta in early human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of fentanyl during pregnancy. Fentanyl should not be used in pregnancy unless clearly necessary.Use of fentanyl during childbirth is not recommended because it should not be used in the management of acute or postoperative pain (see Precautions). Moreover, because fentanyl passes through the placenta, the use of Fentanyl during childbirth might result in respiratory depression in the newborn infant.Fentanyl is excreted into human milk and may cause sedation or respiratory depression in an infant. Therefore, it is not recommended for use in nursing women.Use in Children: Fentanyl was not studied in children <2 years. Fentanyl should be administered only to opioid-tolerant children age ≥2 years. To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl (see Instructions for Use/Handling under Cautions for Usage) and monitor adhesion of the patch closely.Use in Elderly: Data from IV studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged t1/2 and they may be more sensitive to the drug than younger patients. If elderly patients receive fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced iof necessary

Adverse Reactions

In addition to the usual adverse effects associated with opiate therapy, local adverse effects associated with application of transdermal system of fentanyl include erythema, papules, pruritus, and edema at the site of application. Erythema at the site of application is common and may persist for 6 hours or longer following removal of the transdermal system; exfoliative dermatitis and pustules have been reported occasionally. Respiratory depression resulting in hypoventilation is the most serious adverse reaction observed in clinical trials with the transdermal system; this effect occurred in 4 or 2% of patients treated transdermally for post-operative or caner pain, respectively, in these trials. In post-marketing experience, fatal hypoventilation secondary to inappropriate use of fentanyl transdermal system has been reported.

Drug Interaction

Interactions with CYP3A4 Inhibitors: Fentanyl, a high clearance drug, is rapidly and extensively metabolized mainly by CYP3A4. The concomitant use of other CNS depressants (including opioids, sedatives, hypnotics, generals anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages) may produce additive depressant effects; hypoventilation, hypotension, and profound sedation, coma, or death may occur. Therefore, the use of any of these drugs concomitantly with fentanyl requires special patient care and observation.The concomitant use of 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 inhibitors and transdermal fentanyl is not recommended, unless the patient is closely monitored (see Precautions).Monoamine Oxidase Inhibitors (MAOI): Fentanyl is not recommended for use in patients who require the concomitant administration of a MAOI. Severe and unpredictable interaction with MAOIs, involving the potentiation of opiate effects or the potentiation of serotoninergic effects, have been reported. Therefore, fentanyl should not be used within 14 days after discontinuation of treatment with MAOIs.

Storage

Store at temperatures not exceeding 30°C

Description

Each transdermal patch contains: (5.25 cm2) Fentanyl 2.1 mg and (21 cm2) Fentanyl 8.4 mg.Each Fentanyl patch 12- and 50 mcg/hr contains fentanyl 2.1- and 8.4 mg, respectively, and covers an active surface area of 5.25- and 21 cm2, respectively. This product is a transdermal patch providing continuous systemic delivery of fentanyl, a potent opioid analgesic, for 72 hours.

Action

Pharmacology: Pharmacodynamics: Fentanyl is an opioid analgesic, interacting predominantly with the mu-opioid receptor. Its primary therapeutic actions are analgesia and sedation. Minimum effective analgesic serum concentrations of fentanyl in opioid-naïve patients range from 0.3-1.5 ng/mL; side effects increase in frequency at serum concentrations >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: Absorption: This product provides continuous systemic delivery of fentanyl during the 72-hr application 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 initial 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.Distribution: The plasma-protein binding of fentanyl about 84%.Metabolism: Fentanyl is a high clearance drug and is rapidly and extensively metabolized primarily by CYP3A4 in the liver. The major metabolite, norfentanyl, is inactive. Skin does not appear to metabolize 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 Fentanyl patch is removed, serum fentanyl concentrations decline gradually, failing about 50% in about 27 (range 13-22) hrs following a 24-hr application. Following a 72-hr application, the mean t1/2 ranges from 20-27 hrs. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum that is seem after an IV infusion, where the apparent t1/2 is approximately 7 (range 3-12) hrs. Within 72 hrs of IV fentanyl administration, approximately 75% of the fentanyl dose 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.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. In a 2-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumor at subcutaneous doses up to 33 mcg/kg/day in males or 100 mcg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/hr patch based on AUC0-24h comparison).