Fentanyl (transdermal): Difference between revisions

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|authorTag={{Ammu}}
|authorTag={{Ammu}}
|genericName=Fentanyl
|genericName=Fentanyl
|aOrAn=a
|aOrAn=an
|drugClass=[[opioid analgesic]]
|indicationType=treatment
|indicationType=treatment
|indication= persistent, moderate to severe chronic pain  
|indication=persistent, moderate to severe chronic pain
|hasBlackBoxWarning=Yes
|hasBlackBoxWarning=Yes
|adverseReactions=application site reaction, [[diaphoresis]], [[pruritus]], [[abdominal pain]] ([[transdermal]], [[constipation]] (adults, , [[diarrhea]], [[indigestion]] (transdermal, loss of appetite, [[nausea]], [[vomiting]], [[xerostomia]], [[asthenia]], [[confusion ]], [[dizziness]], feeling nervous, [[headache]], [[insomnia]], [[somnolence]], [[psychiatric]]: Anxiety, [[depression]], [[euphoria]], [[hallucinations]], [[upper respiratory infection ]], [[influenza]]-like symptoms
|adverseReactions=application site reaction, [[diaphoresis]], [[pruritus]], [[abdominal pain]] ([[transdermal]], [[constipation]] (adults, , [[diarrhea]], [[indigestion]] (transdermal, loss of appetite, [[nausea]], [[vomiting]], [[xerostomia]], [[asthenia]], [[confusion ]], [[dizziness]], feeling nervous, [[headache]], [[insomnia]], [[somnolence]], [[psychiatric]]: Anxiety, [[depression]], [[euphoria]], [[hallucinations]], [[upper respiratory infection ]], [[influenza]]-like symptoms
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Because of the risk for misuse, abuse, addiction, and overdose, Lazanda is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program.
Because of the risk for misuse, abuse, addiction, and overdose, Lazanda is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program.
|fdaLIADAdult=Indication
|fdaLIADAdult=Indication
Lazanda (fentanyl) nasal spray is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 60 mg of oral morphine/day, 25 mcg of transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for a week or longer. Patients must remain on around-the-clock opioids when taking Lazanda.
Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that:
requires continuous, around-the-clock opioid administration for an extended period of time, and
cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids.
Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr (see DOSAGE AND ADMINISTRATION). Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.


Lazanda is contraindicated for patients who are not already tolerant to opioids because life-threatening respiratory depression and death could occur in patients not taking chronic opioids. For this reason, Lazanda is contraindicated in the management of acute or postoperative pain, including headache/migraine, or dental pain. [4]
Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is contraindicated for use on an as needed basis (i.e., prn), for the management of post-operative or acute pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS).


Lazanda is intended to be prescribed only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain.
An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.


Limitations of Use:
Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction.
 
As a part of the TIRF REMS Access program, Lazanda may be dispensed only to outpatients enrolled in the program. [see WARNINGS AND PRECAUTIONS (5.10)]. For inpatient administration of Lazanda (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient enrollment is not required.
Dosage
Dosage
Healthcare professionals who prescribe Lazanda on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of Lazanda [see WARNINGS AND PRECAUTIONS (5.10)}.
Special Precautions
 
Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse and diversion.
As with all opioids, the safety of patients using such products is dependent on healthcare professionals prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.
 
Open the child-resistant container just prior to product use and always replace the bottle in the child-resistant container between doses.
 
2.1 Dose Titration
The goal of dose titration is to find the individual patient's effective and tolerable dose. The dose of Lazanda is not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and MUST be determined by dose titration.
 
Starting Dose: Individually titrate Lazanda to a dose that provides adequate analgesia with tolerable side effects. Begin treatment of all patients (including those switching from another fentanyl product) using ONE 100 mcg spray of Lazanda (1 spray in one nostril). Due to differences in pharmacokinetic properties and individual variability, do not switch patients on a mcg per mcg basis from any other fentanyl product to Lazanda as Lazanda is not equivalent with any other fentanyl product, nor is Lazanda a generic version of any other fentanyl product.
 
If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg single spray, treat subsequent episodes of breakthrough pain with this dose.
 
Titration steps: If adequate analgesia is not achieved with the first 100 mcg dose, dose escalate in a step-wise manner over consecutive episodes of breakthrough pain until adequate analgesia with tolerable side effects is achieved.
[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
2.2 Maintenance Treatment
Once an appropriate dose has been established, instruct patients to use that dose for each subsequent breakthrough cancer pain episode. Limit Lazanda use to four or fewer doses per day.
 
Patients MUST wait at least 2 hours before treating another episode of breakthrough cancer pain with Lazanda.
 
During any episode of breakthrough cancer pain, if there is inadequate pain relief after 30 minutes following Lazanda dosing or if a separate episode of breakthrough cancer pain occurs before the next dose of Lazanda is permitted (i.e. within 2 hours), the patients may use a rescue medication as directed by their healthcare provider.
 
2.3 Dose Re-Adjustment
If the response (analgesia or adverse reactions) to the titrated Lazanda dose markedly changes, an adjustment of dose may be necessary to ensure that an appropriate dose is maintained.
 
If more than four episodes of breakthrough pain are experienced per day, re-evaluate the dose of the long-acting opioid used for persistent underlying cancer pain. If the long-acting opioid or dose of long-acting opioid is changed, re-evaluate and re-titrate the Lazanda dose as necessary to ensure the patient is on an appropriate dose.
 
Limit the use of Lazanda to treat four or fewer episodes of breakthrough pain per day.
 
It is imperative that any dose re-titration is monitored carefully by a healthcare professional.
 
2.4 Administration of Lazanda
Instruct patients on the proper use of Lazanda.
 
Prime the device before use by spraying into the pouch (4 sprays in total) following the instructions for use in the MEDICATION GUIDE [17.3].
Insert the nozzle of the Lazanda bottle a short distance (about ½ inch or 1 cm) into the nose and point towards the bridge of the nose, tilting the bottle slightly.
Press down firmly on the finger grips until they hear a "click" and the number in the counting window advances by one.
Advise patients that the fine mist spray is not always felt on the nasal mucosal membrane and to rely on the audible click and the advancement of the dose counter to confirm a spray has been administered.
 
2.5 Discontinuation of Therapy
For patients no longer requiring opioid therapy, consider discontinuing Lazanda along with a gradual downward titration of other opioids to minimize possible withdrawal effects.
 
In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, Lazanda therapy can usually be discontinued immediately.
 
|offLabelAdultGuideSupport=
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport=
 
 


There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. The fentanyl transdermal system should not be used if the pouch seal is broken, or the patch is cut, damaged, or changed in any way.


<!--Pediatric Indications and Dosage-->
Each fentanyl transdermal system may be worn continuously for 72 hours. The next patch should be applied to a different skin site after removal of the previous transdermal system.


<!--FDA-Labeled Indications and Dosage (Pediatric)-->
If problems with adhesion of the fentanyl transdermal system occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlaid with a transparent adhesive film dressing (e.g., Bioclusive™ or Tegaderm™).
|fdaLIADPed=
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.


<!--Off-Label Use and Dosage (Pediatric)-->
If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site.


<!--Guideline-Supported Use (Pediatric)-->
Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean half-life of approximately 17 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.
|offLabelPedGuideSupport=


There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING; CLINICAL PHARMACOLOGY, DRUG INTERACTIONS; WARNINGS and PRECAUTIONS for further information).


<!--Non–Guideline-Supported Use (Pediatric)-->
Pediatric patients converting to fentanyl transdermal system with a 25 mcg/hr patch should be opioid-tolerant and receiving at least 60 mg of oral morphine or the equivalent per day. The dose conversion schedule described in TABLE C, and method of titration described below are recommended in opioid-tolerant pediatric patients over 2 years of age with chronic pain (see PRECAUTIONS, PEDIATRIC USE).
|offLabelPedNoGuideSupport=
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.


<!--Contraindications-->
Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.
|contraindications=


<!--Warnings-->
Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric Use ).
|warnings=* 5.1 Respiratory Depression
Serious or fatal respiratory depression can occur even at recommended doses in patients using Lazanda. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, in opioid non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.


Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a "sighing" pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
General Principles
Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that:


5.2 Lazanda and other Fentanyl Products
requires continuous, around-the-clock opioid administration for an extended period of time
Lazanda is NOT equivalent to other fentanyl products used to treat breakthrough pain on a mcg per mcg basis. There are differences in the pharmacokinetics of Lazanda relative to other fentanyl products which could potentially result in clinically important differences in the amount of fentanyl absorbed and could result in a fatal overdose.
cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids.
Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg oral hydromorphone daily, or an equianalgesic dose of another opioid.


When prescribing Lazanda to a patient, DO NOT convert from other fentanyl products. Directions for safely converting patients to Lazanda from other fentanyl products are not currently available. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl). Therefore, for opioid-tolerant patients starting treatment for breakthrough pain, the initial dose of Lazanda is 100 mcg. Individually titrate each patient's dose to provide adequate analgesia while minimizing side effects. [See DOSAGE AND ADMINISTRATION (2.1)]
Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:


When dispensing Lazanda to a patient, DO NOT substitute it for any other fentanyl product prescription.
in patients who are not opioid-tolerant
in the management of acute pain or in patients who require opioid analgesia for a short period of time
in the management of post-operative pain, including use after out-patient or day surgeries (e.g., tonsillectomies)
in the management of mild pain
in the management of intermittent pain (e.g., use on an as needed basis [prn])
(see CONTRAINDICATIONS for further information).


5.3 Information for Patients and Their Caregivers
Safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, PEDIATRIC USE).
Patients and their caregivers must be instructed that Lazanda contains medicine in an amount that could be fatal to a child.


Patients and their caregivers must be instructed to keep both used and unused bottles in their child-resistant container and out of the reach of children at all times. Partially used bottles represent a special risk to children. As soon as they are no longer required, all used, unopened or partially used bottles must be completely emptied of accessible fentanyl solution by spraying the remaining contents into the carbon-lined pouch. The sealed pouch and the empty bottle should be put into the child-resistant container before discarding in the trash. Hands must be washed with soap and water immediately after handling the pouch. [see STORAGE AND HANDLING (16.2), DISPOSAL OF LAZANDA (16.3), and PATIENT/CAREGIVER INSTRUCTIONS (17.1)].
Prescribers should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.


Physicians and dispensing pharmacists must question patients and caregivers specifically about the presence of children in the home on a full-time or visiting basis and counsel accordingly regarding the dangers to children of inadvertent exposure to Lazanda.
With all opioids, the safety of patients using the products is dependent on healthcare practitioners prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.


Lazanda could be fatal to individuals for whom it is not prescribed and for those who are not opioid tolerant.
As with all opioids, dosage should be individualized. The most important factor to be considered in determining the appropriate dose is the extent of pre-existing opioid-tolerance (see BOX WARNING and CONTRAINDICATIONS). Initial doses should be reduced in elderly or debilitated patients (see PRECAUTIONS).


5.4 Additive CNS Depressant Effects
Fentanyl transdermal system should be applied to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site should be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application.
The concomitant use of Lazanda with other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages may produce increased depressant effects (e.g., hypoventilation, hypotension, and profound sedation). Concomitant use with potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors) may increase fentanyl levels, resulting in increased depressant effects [see METABOLIC DRUG INTERACTIONS (7.1)].


Patients on concomitant CNS depressants must be monitored for a change in opioid effects and may require adjustment of the dose of Lazanda.
Fentanyl transdermal system should be applied immediately upon removal from the sealed package. Do not use if the pouch seal is broken. Do not alter the patch (e.g., cut) in any way prior to application and do not use cut or damaged patches.


5.5 Effects on Ability to Drive and Use Machines
The transdermal system should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.
Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Warn patients taking Lazanda of these dangers and counsel them accordingly.


5.6 Chronic Pulmonary Disease
Fentanyl transdermal system should be kept out of the reach of children. Used patches should be folded so that the adhesive side of the patch adheres to itself, then the patch should be flushed down the toilet immediately upon removal. Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed. Unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.
Because potent opioids can cause respiratory depression, cautiously adjust the dose of Lazanda in patients with chronic obstructive pulmonary disease or preexisting medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of Lazanda may further decrease respiratory drive to the point of respiratory failure.


5.7 Head Injuries and Increased Intracranial Pressure
Dose Selection
Administer Lazanda with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury; only use opioids if clinically warranted.
Doses must be individualized based upon the status of each patient and should be assessed at regular intervals after fentanyl transdermal system application. Reduced doses of fentanyl transdermal system are suggested for the elderly and other groups discussed in PRECAUTIONS.


5.8 Cardiac Disease
Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression.  
Intravenous fentanyl may produce bradycardia. Use Lazanda with caution in patients with bradyarrhythmias.


5.9 MAO Inhibitors
In selecting an initial fentanyl transdermal system dose, attention should be given to 1) the daily dose, potency, and characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist-antagonist), 2) the reliability of the relative potency estimates used to calculate the fentanyl transdermal system dose needed (potency estimates may vary with the route of administration), 3) the degree of opioid tolerance and 4) the general condition and medical status of the patient. Each patient should be maintained at the lowest dose providing acceptable pain control.
Lazanda is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. [see NON-METABOLIC DRUG INTERACTIONS (7.2)].


5.10 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) Access Program
Initial Fentanyl Transdermal System Dose Selection
Because of the risk of misuse, abuse, addiction, and overdose [see DRUG ABUSE AND DEPENDENCE (9)], Lazanda is available only through a restricted program under a REMS called the TIRF REMS Access program. Under the TIRF REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. For inpatient administration (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use) of Lazanda, patient and prescriber enrollment is not required.
Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean half-life of approximately 17 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.  


Required components of the TIRF REMS Access program are:
There has been no systematic evaluation of fentanyl transdermal system as an initial opioid analgesic in the management of chronic pain, since most patients in the clinical trials were converted to fentanyl transdermal system from other narcotics. The efficacy of fentanyl transdermal system 12 mcg/hr as an initiating dose has not been determined. In addition, patients who are not opioid-tolerant have experienced hypoventilation and death during use of fentanyl transdermal system. Therefore, fentanyl transdermal system should be used only in patients who are opioid-tolerant.


Healthcare professionals who prescribe Lazanda must review the prescriber educational materials for the TIRF REMS Access program, enroll in the program, and comply with the REMS requirements.
To convert patients from oral or parenteral opioids to fentanyl transdermal system, use TABLE C:
To receive Lazanda, outpatients must understand the risks and benefits and sign a Patient-Prescriber Agreement.
Pharmacies that dispense Lazanda must enroll in the program and agree to comply with the REMS requirements.
Wholesalers and distributers that distribute Lazanda must enroll in the program and distribute only to authorized pharmacies.
|clinicalTrials=6.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


The safety of Lazanda has been evaluated in a total of 523 opioid-tolerant patients with breakthrough cancer pain. The average duration of therapy in patients in the long-term study was 73 days, with 153 patients being treated for over 3 months. Patients continuing into the open-label extension period of the safety study have been treated for up to 26 months.
Alternatively, for adult and pediatric patients taking opioids or doses not listed in TABLE C, use the following methodology:
 
Calculate the previous 24-hour analgesic requirement.
The most commonly observed adverse events seen with Lazanda are typical of opioid side effects, such as nausea, constipation, somnolence, and headache. Expect opioid side effects and manage them accordingly.
Convert this amount to the equianalgesic oral morphine dose using TABLE D.
 
TABLE E displays the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding fentanyl transdermal system dose. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than every 3 days after the initial dose or than every 6 days thereafter) until analgesic efficacy is attained. The recommended starting dose when converting from other opioids to fentanyl transdermal system is likely too low for 50% of patients. This starting dose is recommended to minimize the potential for overdosing patients with the first dose. For delivery rates in excess of 100 mcg/hr, multiple systems may be used.
The clinical trials of Lazanda were designed to evaluate safety and efficacy in treating breakthrough cancer pain; all patients were also taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone, or transdermal fentanyl, for their persistent cancer pain. The adverse reaction data presented in Table 1 reflect the actual percentage of patients experiencing each adverse effect among patients who received Lazanda for breakthrough cancer pain along with a concomitant opioid for persistent cancer pain. There has been no attempt to correct for concomitant use of other opioids, duration of Lazanda therapy, or cancer-related symptoms. Adverse events are included regardless of causality or severity. Table 1 lists adverse reactions with an overall frequency of 5% or greater within the total population that occurred during titration by maximum dose received. The ability to assign Lazanda a dose-response relationship to these adverse events is limited by the titration schemes used in these studies.
[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|postmarketing=Eye disorders: dry eye, swelling, ptosis, strabismus
The majority of patients are adequately maintained with fentanyl transdermal system administered every 72 hours. Some patients may not achieve adequate analgesia using this dosing interval and may require systems to be applied every 48 hours rather than every 72 hours. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen. Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.
Blood and Lymphatic System Disorders: anemia, neutropenia
Cardiac Disorders: cardiorespiratory arrest
Gastrointestinal Disorders: vomiting, nausea, constipation, diarrhea, abdominal pain, gastritis, ascites, dry mouth, dyspepsia, mouth ulcer, proctalgia
General Disorders and Administration Site Conditions: pyrexia, fatigue, edema peripheral, asthenia, edema
Hepatobiliary Disorders: jaundice
Immune System Disorders: hypersensitivity
Infections and Infestations: urinary tract infection, pneumonia, nasopharyngitis, infection, rhinitis, upper respiratory tract infection, bronchitis
Injury, Poisoning and Procedural Complications: fall
Investigations: weight decreased, blood alkaline phosphatase increased
Metabolism and Nutrition Disorders: dehydration, decreased appetite, hyperglycemia, anorexia
Musculoskeletal and Connective Tissue Disorders: back pain, pain in extremity, arthralgia
Nervous System Disorders: dizziness, somnolence, headache, dysgeusia
Psychiatric Disorders: anxiety, insomnia, depression, confusional state, disorientation, agitation
Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, cough, pharyngolaryngeal pain, nasal discomfort, rhinorrhea, nasal congestion, postnasal drip, pulmonary embolism
Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, decubitus ulcer, mouth ulceration
Vascular Disorders: hypertension, deep vein thrombosis
|drugInteractions=* 7.1 Metabolic Drug Interactions
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when Lazanda is given concurrently with agents that affect CYP3A4 activity.


CYP3A4 inhibitors
Because of the increase in serum fentanyl concentration over the first 24 hours following initial system application, the initial evaluation of the maximum analgesic effect of fentanyl transdermal system cannot be made before 24 hours of wearing. The initial fentanyl transdermal system dose may be increased after 3 days (see DOSAGE AND ADMINISTRATION, DOSE TITRATION).


The concomitant use of Lazanda with CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a potentially dangerous increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving Lazanda who begin therapy with, or increase the dose of, CYP3A4 inhibitors are to be carefully monitored for signs of opioid toxicity over an extended period of time. Increase dose conservatively [see WARNINGS AND PRECAUTIONS (5.4)].
During the initial application of fentanyl transdermal system, patients should use short-acting analgesics as needed until analgesic efficacy with fentanyl transdermal system is attained. Thereafter, some patients still may require periodic supplemental doses of other short-acting analgesics for “breakthrough” pain.


CYP3A4 inducers
Dose Titration
The recommended initial fentanyl transdermal system dose based upon the daily oral morphine dose is conservative, and 50% of patients are likely to require a dose increase after initial application of fentanyl transdermal system. The initial fentanyl transdermal system dose may be increased after 3 days based on the daily dose of supplemental opioid analgesics required by the patient in the second or third day of the initial application.


The concomitant use of Lazanda with CYP3A4 inducers (e.g., barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, or troglitazone) may result in a decrease in fentanyl plasma concentrations, which could decrease the efficacy of Lazanda. Patients receiving Lazanda who stop therapy with, or decrease the dose of, CYP3A4 inducers may experience sudden increase in fentanyl plasma concentrations and are to be monitored for signs of increased Lazanda activity. Adjust the dose of Lazanda accordingly.
Physicians are advised that it may take up to 6 days after increasing the dose of fentanyl transdermal system for the patient to reach equilibrium on the new dose (see graph in CLINICAL PHARMACOLOGY). Therefore, patients should wear a higher dose through two applications before any further increase in dosage is made on the basis of the average daily use of a supplemental analgesic.


7.2 Non-metabolic Drug Interactions
Appropriate dosage increments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12.5 mcg/hr increase in fentanyl transdermal system dose.
Agents used to treat Allergic Rhinitis


The presence of allergic rhinitis is not expected to affect Lazanda absorption. However, co-administration of a vasoconstrictive nasal decongestant such as oxymetazoline to treat allergic rhinitis leads to lower peak plasma concentrations and a delayed Tmax of fentanyl that may cause Lazanda to be less effective in patients with allergic rhinitis who use such decongestants, thus potentially impairing pain management. Additionally, in view of the possibility that the titration of a patient while they are experiencing an acute episode of rhinitis could lead to incorrect dose identification (particularly if they are using a vasoconstrictive decongestant), titration under these circumstances must be avoided [see CLINICAL PHARMACOLOGY (12.3)].
Discontinuation of Fentanyl Transdermal System
To convert patients to another opioid, remove fentanyl transdermal system and titrate the dose of the new analgesic based upon the patient’s report of pain until adequate analgesia has been attained. Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion or dose adjustment. For patients requiring discontinuation of opioids, a gradual downward titration is recommended since it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.


MAO inhibitor
Tables C, D, and E should not be used to convert from fentanyl transdermal system to other therapies. Because the conversion to fentanyl transdermal system is conservative, use of Tables C, D, and E for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Fentanyl (transdermal) in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Fentanyl (transdermal) in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Fentanyl (transdermal) in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Fentanyl (transdermal) in pediatric patients.
|contraindications=Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:


Concomitant use of Lazanda with an MAO inhibitor, or within 14 days of discontinuing an MAO inhibitor, is not recommended.
in patients who are not opioid-tolerant
|FDAPregCat=C
in the management of acute pain or in patients who require opioid analgesia for a short period of time
|useInPregnancyFDA=* There are no adequate and well-controlled studies in pregnant women.
in the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies)
in the management of mild pain
in the management of intermittent pain (e.g., use on an as needed basis [prn])
in situations of significant respiratory depression, especially in unmonitored settings where there is a lack of resuscitative equipment
in patients who have acute or severe bronchial asthma
Fentanyl transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus.


Use Lazanda during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.
Fentanyl transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or any components of this product.
|warnings=Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyl transdermal system if the pouch seal is broken or the patch is cut, damaged, or changed in any way.


Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.
The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, PEDIATRIC USE).


In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.
Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean half-life is approximately 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.


Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists.


Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for Lazanda.
All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. 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 transdermal system increased mean fentanyl AUC values by 120% and mean Cmax values by 61%.


Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21 of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic. The high dose was approximately 3 times the human dose of 800 mcg per pain episode on a mg/m2 basis. Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation days 6 to 18 was embryo or fetal toxic and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but it was not teratogenic.
Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose should be adjusted if necessary.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''


There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
Death and other serious medical problems have occurred when people were accidentally exposed to fentanyl transdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal system from an adult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while the caregiver was applying or removing the patch.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=There are no adequate and well-controlled studies in pregnant women.


Use Lazanda during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.
Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.


Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures in newborn infants characteristic of neonatal abstinence syndrome.
Misuse, Abuse and Diversion of Opioids
Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.


In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers.
Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when prescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.


Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
Fentanyl transdermal system has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION).


Fentanyl is embryocidal in rats as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for Lazanda.
Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.


Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21 of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic. The high dose was approximately 3 times the human dose of 800 mcg per pain episode on a mg/m2 basis. Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation days 6 to 18 was embryo or fetal toxic and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but it was not teratogenic.
Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.


<!--Administration and Monitoring-->
Hypoventilation (Respiratory Depression)
|administration=* Nasal
Serious or life-threatening hypoventilation may occur at any time during the use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy and following increases in dose.
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.


Because significant amounts of fentanyl continue to be absorbed from the skin for 17 hours or more after the patch is removed, hypoventilation may persist beyond the removal of fentanyl transdermal system. Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized.


<!--IV Compatibility-->
The use of concomitant CNS active drugs requires special patient care and observation.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.


<!--Overdosage-->
Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl transdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.
|overdose=10.1 Clinical Presentation
The manifestations of overdosage with Lazanda are expected to be similar to those for intravenous fentanyl and other opioids, and are an extension of its pharmacological actions, with the most serious significant adverse effect being hypoventilation [see CLINICAL PHARMACOLOGY (12)].


10.2 Immediate Management
Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
Immediate management of opioid overdose includes removal of the Lazanda pectin gel, if still in the nostril, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, ventilatory status, and circulatory status.


10.3 Treatment of Overdosage (Accidental Ingestion) in Opioid Non-Tolerant Patients
Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.
Provide ventilatory support, obtain intravenous access, and administer naloxone or other opioid antagonists as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist's action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use.


10.4 Treatment of Overdose in Opioid-Tolerant Patients
Chronic Pulmonary Disease
Provide ventilatory support and obtain intravenous access as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome.
Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl transdermal system should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.


10.5 General Considerations for Overdose
Head Injuries and Increased Intracranial Pressure
Management of severe Lazanda overdose includes: securing a patent airway, assisting or controlling ventilation, and establishing intravenous access. In the presence of hypoventilation or apnea, assist or control ventilation, and administer oxygen as indicated.
Fentanyl transdermal system should not be used 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. Opioids may obscure the clinical course of patients with head injury. Fentanyl transdermal system should be used with caution in patients with brain tumors.


Carefully observe and appropriately manage overdosed patients until their clinical condition is well controlled.
Interactions with Other CNS Depressants
The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.


Although muscle rigidity interfering with respiration has not been observed following the use of Lazanda, this is possible with fentanyl and other opioids. If it occurs, manage by the use of assisted or controlled ventilation, by administration of an opioid antagonist, and, as a final alternative, by the administration of a neuromuscular blocking agent.
Interactions with Alcohol and Drugs of Abuse
|drugBox={{drugbox2
Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
| Watchedfields = changed
| verifiedrevid = 443760208
| IUPAC_name = ''N''-(1-(2-phenylethyl)-4-piperidinyl)-''N''-phenylpropanamide
| image = Fentanyl wiki1.png
| width = 200
| image2 = Fentanylwiki 2.gif
| width2 = 200


<!--Clinical data-->
Interactions with CYP3A4 Inhibitors
| tradename = Actiq, Duragesic, Fentora, Sublimaze ''and others''
The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted
| Drugs.com = {{drugs.com|monograph|fentanyl-citrate}}
|clinicalTrials=Although fentanyl transdermal system use in post-operative or acute pain and in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system was originally evaluated in 357 post-operative adult patients for 1 to 3 days and 153 cancer patients for a total of 510 patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year.
| pregnancy_AU = C
| pregnancy_US = C
| legal_AU = S8
| legal_UK = Class A
| legal_US = Schedule II
| dependency_liability = Moderate – high
| routes_of_administration = [[Transdermal patch|TD]], [[Intramuscular injection|IM]], [[Intravenous therapy|IV]], [[transmucosal|oral transmucosal]], [[sublingual]], [[buccal mucosa|buccal]]


<!--Pharmacokinetic data-->
Hypoventilation was the most serious adverse reaction observed in 13 (4%) post-operative patients and in 3 (2%) of the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.
| bioavailability = 92% (transdermal)<br />89% (intranasal)<br />50% (buccal)<br />33% (ingestion)
| protein_bound = 80–85%
| metabolism = [[hepatic]], primarily by [[CYP3A4]]
| elimination_half-life = (IV)= 10-20&nbsp;mins (T1/2 β)<br /> 2-4&nbsp;hours (T1/2 ɣ)<br />Intranasal = 6.5&nbsp;mins<br />Transdermal = 20–27&nbsp;h<ref>[http://www.duragesic.com/ Janssen Pharmaceuticals (Duragesic)]</ref>
| excretion = 60% Urinary (metabolites, <10% unchanged drug)<ref name="pmid4655287">{{cite journal | author = Hess R, Stiebler G, Herz A | title = Pharmacokinetics of fentanyl in man and the rabbit | journal = Eur. J. Clin. Pharmacol. | volume = 4 | issue = 3 | pages = 137–41 |date=June 1972 | pmid = 4655287 | doi = 10.1007/BF00561135 }}</ref>


<!--Identifiers-->
Various adverse events were reported; a causal relationship to fentanyl transdermal system was not always determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who received fentanyl transdermal system. There has been no attempt to correct for a placebo effect, concomitant use of other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials.
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 437-38-7
| ATC_prefix = N01
| ATC_suffix = AH01
| ATC_supplemental =  {{ATC|N02|AB03}}
| PubChem = 3345
| IUPHAR_ligand = 1626
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00813
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3228
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = UF599785JZ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00320
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 119915
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 596


<!--Chemical data-->
Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in TABLE 1; similar reactions were seen in the 357 post-operative patients.
| C=22 | H=28 | N=2 | O=1
| molecular_weight = 336.471 g/mol
| smiles = O=C(CC)N(C1CCN(CC1)CCC2=CC=CC=C2)C3=CC=CC=C3
| InChI = 1/C22H28N2O/c1-2-22(25)24(20-11-7-4-8-12-20)21-14-17-23(18-15-21)16-13-19-9-5-3-6-10-19/h3-12,21H,2,13-18H2,1H3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C22H28N2O/c1-2-22(25)24(20-11-7-4-8-12-20)21-14-17-23(18-15-21)16-13-19-9-5-3-6-10-19/h3-12,21H,2,13-18H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PJMPHNIQZUBGLI-UHFFFAOYSA-N
| melting_point = 87.5
}}
|mechAction=*


<!--Structure-->
In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.
|structure=*


: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in children as young as 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), and nausea (24%).


<!--Pharmacodynamics-->
Adverse events reported in pediatric patients at a rate of ≥1% are presented in TABLE 1.
|PD=Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence, respiratory depression and death.
[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
The following adverse effects have been reported in less than 1% of the 510 adult post-operative and cancer patients studied:
Cardiovascular: bradycardia
Digestive: abdominal distention
Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility
Respiratory: stertorous breathing, asthma, respiratory disorder
Skin and Appendages, General: exfoliative dermatitis, pustules
Special Senses: amblyopia
Urogenital: bladder pain, oliguria, urinary frequency


Analgesia: In general, the effective concentration and the concentration at which toxicity occurs increase with increasing tolerance to any and all opioids.
|postmarketing=The following adverse reactions have been reported in association with the use of fentanyl transdermal system and not reported in the pre-marketing adverse reactions section above:
Body as a Whole: edema
Cardiovascular: tachycardia
Metabolic and Nutritional: weight loss
Special Senses: blurred vision
Urogenital: decreased libido, anorgasmia, ejaculatory difficulty


The rate of development of tolerance varies widely among individuals. As a result, individually titrate the dose of Lazanda to achieve the desired effect. [see DOSAGE AND ADMINISTRATION (2)].
|drugInteractions=Agents Affecting Cytochrome P450 3A4 Isoenzyme System


Central Nervous System: The precise mechanism of the analgesic action is unknown although fentanyl is known to be a mu-opioid receptor agonist. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when fentanyl transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadminstration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING; CLINICAL PHARMACOLOGY, DRUG INTERACTIONS; WARNINGS and DOSAGE AND ADMINISTRATION for further information).  


Fentanyl produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation.
Central Nervous System Depressants


Fentanyl causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).
The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.


Gastrointestinal System: Fentanyl causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary, and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
MAO Inhibitors


Cardiovascular System: Fentanyl may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Fentanyl transdermal system is not recommended for use in patients who have received MAOI within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
|FDAPregCat=C
|useInPregnancyFDA=No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.


Endocrine System: Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species (e.g., rats and dogs). Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.
The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 mcg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.


Respiratory System: All opioid mu-receptor agonists, including fentanyl, produce dose-dependent respiratory depression. The risk of respiratory depression is less in patients receiving chronic opioid therapy who develop tolerance to respiratory depression and other opioid effects.
Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis).


Serious or fatal respiratory depression can occur even at recommended doses. Fentanyl depresses the cough reflex as a result of its CNS activity. Although not observed with Lazanda, in clinical trials, fentanyl given rapidly by intravenous injection in large doses has interfered with respiration by causing rigidity in the muscles of respiration.
There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
|PK=: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|useInPed=The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/hr and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. Approximately 90% of the total daily opioid requirement (fentanyl transdermal system plus rescue medication) was provided by fentanyl transdermal system.
n a pharmacokinetic study that evaluated multiple-dose pharmacokinetics of Lazanda when two doses of Lazanda are administered in the same nostril and are separated by a 1, 2 or 4 h time lapse, Cmax2 (Cmax after second administration) was greater than Cmax1 (Cmax after first administration), by 30% when Lazanda was administered 1 h apart, by 25% when Lazanda was administered 2 h apart and by 10% when Lazanda was administered 4 h apart. Based on these results and based on Tmax range of Lazanda observed across pharmacokinetic studies, and frequency of breakthrough pain episodes in a cancer population, a waiting period of 2 h between two consecutive doses of Lazanda is recommended [see DOSAGE AND ADMINISTRATION (2)].


In a pharmacokinetic study to evaluate differences in Lazanda absorption in individuals with induced allergic (seasonal) rhinitis, no clinically meaningful differences were observed in rate or extent of exposure to fentanyl, when compared to the Asymptomatic (Unchallenged) state, indicating that presence of allergic rhinitis does not affect Lazanda absorption. This study also assessed differences in Lazanda absorption, if any, when co-administered with oxymetazoline, a nasal decongestant in subjects undergoing treatment for seasonal allergic rhinitis. Mean Cmax values for Treated arm (Rhinitis treated with oxymetazoline) were about 32% and 40% lower and mean AUCt values were about 10% and 17% lower for Ragweed and Tree pollen induced cohorts respectively as compared to the Asymptomatic arm in each cohort. In addition, mean Tmax of Lazanda in the Treated arm was 0.75 h (range 0.08-3 h) for the Ragweed pollen induced cohort and 1.25 h (range 0.08-3 h) for Tree pollen induced cohort as compared to 0.25 h (0.17-1 h) and 0.33 h (0.17-2 h) for the Asymptomatic arm in each cohort respectively. These results indicate that co-administration with oxymetazoline leads to lower peak plasma concentrations and delayed Tmax of Lazanda [see DRUG INTERACTIONS (7.2)].
|useInGeri=Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.


Distribution: Fentanyl is highly lipophilic. The plasma protein binding of fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to some extent. The mean volume of distribution at steady state (Vss) was 4 L/kg.
Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.


Metabolism: The metabolic pathways following intranasal administration of Lazanda have not been characterized in clinical studies. The progressive decline of fentanyl plasma concentrations results from the uptake of fentanyl in the tissues and biotransformation in the liver. Fentanyl is metabolized in the liver and in the intestinal mucosa to norfentanyl by cytochrome P450 3A4 isoform. In animal studies, norfentanyl was not found to be pharmacologically active.
Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance
|administration=Transdermal
|overdose=Clinical Presentation
The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most serious significant effect being hypoventilation.


Elimination: The disposition of fentanyl following intranasal administration of Lazanda has not been characterized in a mass balance study. Fentanyl is primarily (more than 90%) eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Less than 7% of the administered dose is excreted unchanged in the urine, and only about 1% is excreted unchanged in the feces. The metabolites are mainly excreted in the urine, while fecal excretion is less important.
Treatment
For the management of hypoventilation, immediate countermeasures include removing the fentanyl transdermal system and physically or verbally stimulating the patient. These actions can be followed by administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following an overdose may be longer than the effects of the narcotic antagonist’s action (the half-life of naloxone ranges from 30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibility of re-narcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and the release of catecholamines.


The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h.
Always ensure a patent airway is established and maintained, administer oxygen and assist or control respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body temperature and fluid intake should be maintained.
|nonClinToxic=Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl.


Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. typhimurium or E. coli, or the mouse lymphoma mutagenesis assay, and was not clastogenic in the in vivo mouse micronucleus assay.
If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy.
|PD=Because of the risk for serious or life-threatening hypoventilation, fentanyl transdermal system is CONTRAINDICATED in the treatment of post-operative and acute pain and in patients who are not opioid-tolerant. In clinical trials of 357 patients with acute pain treated with fentanyl transdermal system, 13 patients experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in patients weighing less than 63 kg (9 of 13). Although patients with impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system.


Fentanyl has been shown to impair fertility in rats at doses of 30 mcg/kg subcutaneously. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for Lazanda.
While most patients using fentanyl transdermal system chronically develop tolerance to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during therapy.
|clinicalStudies=The efficacy of Lazanda was evaluated in one clinical trial in opioid tolerant adult patients experiencing breakthrough cancer pain. Breakthrough cancer pain was defined as a transient flare of moderate-to-severe pain occurring in patients experiencing persistent cancer pain otherwise controlled with maintenance doses of opioid medications including at least 60 mg of oral morphine/day or an equianalgesic dose of another opioid (which could be fentanyl) for a week or longer. All patients were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain.


The clinical trial included an open-label titration phase where a dose was identified that provided adequate analgesia with tolerable side effects, within the range of 100 to 800 mcg. In the double-blind, placebo-controlled portion of the study, patients who were titrated to an adequate dose were randomized to a blinded sequence of 10 treatments with 7 being the identified dose of Lazanda and 3 being placebo.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive usual doses of opioids or other CNS drugs associated with hypoventilation in addition to fentanyl transdermal system. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy.


Of the patients who enrolled in the study, 73% achieved an adequate dose during the titration phase, 6% withdrew for lack of effective pain relief, and 5% withdrew due to adverse events.
The use of fentanyl transdermal system should be monitored by clinical evaluation, especially within the initial 24 to 72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older.


The distribution of final titrated doses is shown in Table 4. The final titrated dose of Lazanda for breakthrough pain was not predicted from the daily maintenance dose of opioid used to manage the persistent cancer pain and, therefore, the dose was determined by titration starting at 100 mcg.
|PK=Fentanyl transdermal system is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the copolymer release membrane and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]


While there is variation in dose delivered among patients, the nominal flux of the systems (25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient.


|howSupplied=* Lazanda is supplied in a 5.3 ml capacity clear glass bottle with an attached metered-dose nasal spray pump incorporating a visual and audible spray counter, and a protective dust cover. Each bottle contains a net fill weight of 1.57 grams and, after priming, delivers 8 sprays. The pump will remain primed for up to 5 days after priming or use. The nasal spray delivers 8 full sprays. There are 2 product strengths and each 100 mcL spray contains either 100 mcg or 400 mcg of fentanyl. Each bottle is supplied in a child-resistant container.
Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 24 and 72 hours after initial application (see TABLE A). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of 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. Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.  
[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|howSupplied=[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]


Bottles in their child-resistant containers are supplied in cartons containing 1 or 4 bottles with instructions for use.
Safety and Handling
Fentanyl transdermal system is supplied in sealed transdermal systems which pose little risk of exposure to healthcare workers. Do not use a fentanyl transdermal system if the pouch seal is broken or the patch is cut, damaged, or changed in any way.  


Each carton contains one carbon-lined pouch per bottle for disposal of priming sprays, unwanted doses and residual fentanyl solution.
KEEP FENTANYL TRANSDERMAL SYSTEM OUT OF THE REACH OF CHILDREN AND PETS.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|storage=Store in original unopened pouch. Store up to 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Apply immediately after removal from individually sealed pouch. Do not use if the pouch seal is broken. For transdermal use only.  
 
|packLabel=[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
 
[[File:XXXXX.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|packLabel=<!--Patient Counseling Information-->
|alcohol=Alcohol-Fentanyl (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|fdaPatientInfo=There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
|brandNames=* FENTANYL TRANSDERMAL SYSTEM<ref>{{Cite web | title = FENTANYL TRANSDERMAL SYSTEM- fentanyl patch, extended release    | url =http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=67cb9ea4-5adb-4a3a-9568-266b6f472078 }}</ref>
 
<!--Precautions with Alcohol-->
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
 
<!--Brand Names-->
|brandNames=* LAZANDA®<ref>{{Cite web | title = LAZANDA- fentanyl citrate spray | url =http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39531d0c-db12-4627-81c9-6563076b637b }}</ref>


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|drugShortage=
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[[Category:Drug]]

Revision as of 14:11, 25 May 2015

Fentanyl (transdermal)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Disclaimer

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Black Box Warning

WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL RESPIRATORY DEPRESSION
See full prescribing information for complete Boxed Warning.
Fatal respiratory depression has occurred in patients treated with immediate-release transmucosal fentanyl, including following use in opioid non-tolerant patients and improper dosing. The substitution of Lazanda for any other fentanyl product may result in fatal overdose.

Due to the risk of respiratory depression, Lazanda is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see CONTRAINDICATIONS (4)]

Lazanda must be kept out of reach of children. [see PATIENT COUNSELING INFORMATION (17.1) and HOW SUPPLIED/STORAGE AND HANDLING (16.1)]

The concomitant use of Lazanda with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see DRUG INTERACTIONS (7)].

MEDICATION ERRORS

Substantial differences exist in the pharmacokinetic profile of Lazanda compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.

When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to Lazanda. (2.1) When dispensing, do not substitute a Lazanda prescription for other fentanyl products. ABUSE POTENTIAL

Lazanda contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Lazanda can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Lazanda in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Because of the risk for misuse, abuse, addiction, and overdose, Lazanda is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program.

Overview

Fentanyl (transdermal) is an opioid analgesic that is FDA approved for the treatment of persistent, moderate to severe chronic pain. There is a Black Box Warning for this drug as shown here. Common adverse reactions include application site reaction, diaphoresis, pruritus, abdominal pain (transdermal, constipation (adults, , diarrhea, indigestion (transdermal, loss of appetite, nausea, vomiting, xerostomia, asthenia, confusion , dizziness, feeling nervous, headache, insomnia, somnolence, psychiatric: Anxiety, depression, euphoria, hallucinations, upper respiratory infection , influenza-like symptoms.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indication Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that: requires continuous, around-the-clock opioid administration for an extended period of time, and cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids. Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr (see DOSAGE AND ADMINISTRATION). Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is contraindicated for use on an as needed basis (i.e., prn), for the management of post-operative or acute pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS).

An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Dosage Special Precautions Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse and diversion.

Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. The fentanyl transdermal system should not be used if the pouch seal is broken, or the patch is cut, damaged, or changed in any way.

Each fentanyl transdermal system may be worn continuously for 72 hours. The next patch should be applied to a different skin site after removal of the previous transdermal system.

If problems with adhesion of the fentanyl transdermal system occur, the edges of the patch may be taped with first aid tape. If problems with adhesion persist, the patch may be overlaid with a transparent adhesive film dressing (e.g., Bioclusive™ or Tegaderm™).

If the patch falls off before 72 hours, dispose of it by folding in half and flushing down the toilet. A new patch may be applied to a different skin site.

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean half-life of approximately 17 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.

The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING; CLINICAL PHARMACOLOGY, DRUG INTERACTIONS; WARNINGS and PRECAUTIONS for further information).

Pediatric patients converting to fentanyl transdermal system with a 25 mcg/hr patch should be opioid-tolerant and receiving at least 60 mg of oral morphine or the equivalent per day. The dose conversion schedule described in TABLE C, and method of titration described below are recommended in opioid-tolerant pediatric patients over 2 years of age with chronic pain (see PRECAUTIONS, PEDIATRIC USE).

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.

Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric Use ).

General Principles Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that:

requires continuous, around-the-clock opioid administration for an extended period of time cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids. Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg oral hydromorphone daily, or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:

in patients who are not opioid-tolerant in the management of acute pain or in patients who require opioid analgesia for a short period of time in the management of post-operative pain, including use after out-patient or day surgeries (e.g., tonsillectomies) in the management of mild pain in the management of intermittent pain (e.g., use on an as needed basis [prn]) (see CONTRAINDICATIONS for further information).

Safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, PEDIATRIC USE).

Prescribers should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

With all opioids, the safety of patients using the products is dependent on healthcare practitioners prescribing them in strict conformity with their approved labeling with respect to patient selection, dosing, and proper conditions for use.

As with all opioids, dosage should be individualized. The most important factor to be considered in determining the appropriate dose is the extent of pre-existing opioid-tolerance (see BOX WARNING and CONTRAINDICATIONS). Initial doses should be reduced in elderly or debilitated patients (see PRECAUTIONS).

Fentanyl transdermal system should be applied to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. In young children and persons with cognitive impairment, adhesion should be monitored and the upper back is the preferred location to minimize the potential of inappropriate patch removal. Hair at the application site should be clipped (not shaved) prior to system application. If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. Allow the skin to dry completely prior to patch application.

Fentanyl transdermal system should be applied immediately upon removal from the sealed package. Do not use if the pouch seal is broken. Do not alter the patch (e.g., cut) in any way prior to application and do not use cut or damaged patches.

The transdermal system should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.

Fentanyl transdermal system should be kept out of the reach of children. Used patches should be folded so that the adhesive side of the patch adheres to itself, then the patch should be flushed down the toilet immediately upon removal. Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed. Unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.

Dose Selection Doses must be individualized based upon the status of each patient and should be assessed at regular intervals after fentanyl transdermal system application. Reduced doses of fentanyl transdermal system are suggested for the elderly and other groups discussed in PRECAUTIONS.

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression.

In selecting an initial fentanyl transdermal system dose, attention should be given to 1) the daily dose, potency, and characteristics of the opioid the patient has been taking previously (e.g., whether it is a pure agonist or mixed agonist-antagonist), 2) the reliability of the relative potency estimates used to calculate the fentanyl transdermal system dose needed (potency estimates may vary with the route of administration), 3) the degree of opioid tolerance and 4) the general condition and medical status of the patient. Each patient should be maintained at the lowest dose providing acceptable pain control.

Initial Fentanyl Transdermal System Dose Selection Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean half-life of approximately 17 hours, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.

There has been no systematic evaluation of fentanyl transdermal system as an initial opioid analgesic in the management of chronic pain, since most patients in the clinical trials were converted to fentanyl transdermal system from other narcotics. The efficacy of fentanyl transdermal system 12 mcg/hr as an initiating dose has not been determined. In addition, patients who are not opioid-tolerant have experienced hypoventilation and death during use of fentanyl transdermal system. Therefore, fentanyl transdermal system should be used only in patients who are opioid-tolerant.

To convert patients from oral or parenteral opioids to fentanyl transdermal system, use TABLE C:

Alternatively, for adult and pediatric patients taking opioids or doses not listed in TABLE C, use the following methodology: Calculate the previous 24-hour analgesic requirement. Convert this amount to the equianalgesic oral morphine dose using TABLE D. TABLE E displays the range of 24-hour oral morphine doses that are recommended for conversion to each fentanyl transdermal system dose. Use this table to find the calculated 24-hour morphine dose and the corresponding fentanyl transdermal system dose. Initiate fentanyl transdermal system treatment using the recommended dose and titrate patients upwards (no more frequently than every 3 days after the initial dose or than every 6 days thereafter) until analgesic efficacy is attained. The recommended starting dose when converting from other opioids to fentanyl transdermal system is likely too low for 50% of patients. This starting dose is recommended to minimize the potential for overdosing patients with the first dose. For delivery rates in excess of 100 mcg/hr, multiple systems may be used.

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The majority of patients are adequately maintained with fentanyl transdermal system administered every 72 hours. Some patients may not achieve adequate analgesia using this dosing interval and may require systems to be applied every 48 hours rather than every 72 hours. An increase in the fentanyl transdermal system dose should be evaluated before changing dosing intervals in order to maintain patients on a 72-hour regimen. Dosing intervals less than every 72 hours were not studied in children and adolescents and are not recommended.

Because of the increase in serum fentanyl concentration over the first 24 hours following initial system application, the initial evaluation of the maximum analgesic effect of fentanyl transdermal system cannot be made before 24 hours of wearing. The initial fentanyl transdermal system dose may be increased after 3 days (see DOSAGE AND ADMINISTRATION, DOSE TITRATION).

During the initial application of fentanyl transdermal system, patients should use short-acting analgesics as needed until analgesic efficacy with fentanyl transdermal system is attained. Thereafter, some patients still may require periodic supplemental doses of other short-acting analgesics for “breakthrough” pain.

Dose Titration The recommended initial fentanyl transdermal system dose based upon the daily oral morphine dose is conservative, and 50% of patients are likely to require a dose increase after initial application of fentanyl transdermal system. The initial fentanyl transdermal system dose may be increased after 3 days based on the daily dose of supplemental opioid analgesics required by the patient in the second or third day of the initial application.

Physicians are advised that it may take up to 6 days after increasing the dose of fentanyl transdermal system for the patient to reach equilibrium on the new dose (see graph in CLINICAL PHARMACOLOGY). Therefore, patients should wear a higher dose through two applications before any further increase in dosage is made on the basis of the average daily use of a supplemental analgesic.

Appropriate dosage increments should be based on the daily dose of supplementary opioids, using the ratio of 45 mg/24 hours of oral morphine to a 12.5 mcg/hr increase in fentanyl transdermal system dose.

Discontinuation of Fentanyl Transdermal System To convert patients to another opioid, remove fentanyl transdermal system and titrate the dose of the new analgesic based upon the patient’s report of pain until adequate analgesia has been attained. Upon system removal, 17 hours or more are required for a 50% decrease in serum fentanyl concentrations. Opioid withdrawal symptoms (such as nausea, vomiting, diarrhea, anxiety, and shivering) are possible in some patients after conversion or dose adjustment. For patients requiring discontinuation of opioids, a gradual downward titration is recommended since it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal.

Tables C, D, and E should not be used to convert from fentanyl transdermal system to other therapies. Because the conversion to fentanyl transdermal system is conservative, use of Tables C, D, and E for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Fentanyl (transdermal) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Fentanyl (transdermal) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Fentanyl (transdermal) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Fentanyl (transdermal) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Fentanyl (transdermal) in pediatric patients.

Contraindications

Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:

in patients who are not opioid-tolerant in the management of acute pain or in patients who require opioid analgesia for a short period of time in the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies) in the management of mild pain in the management of intermittent pain (e.g., use on an as needed basis [prn]) in situations of significant respiratory depression, especially in unmonitored settings where there is a lack of resuscitative equipment in patients who have acute or severe bronchial asthma Fentanyl transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus.

Fentanyl transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or any components of this product.

Warnings

WARNING: RISK OF RESPIRATORY DEPRESSION, MEDICATION ERRORS, ABUSE POTENTIAL RESPIRATORY DEPRESSION
See full prescribing information for complete Boxed Warning.
Fatal respiratory depression has occurred in patients treated with immediate-release transmucosal fentanyl, including following use in opioid non-tolerant patients and improper dosing. The substitution of Lazanda for any other fentanyl product may result in fatal overdose.

Due to the risk of respiratory depression, Lazanda is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see CONTRAINDICATIONS (4)]

Lazanda must be kept out of reach of children. [see PATIENT COUNSELING INFORMATION (17.1) and HOW SUPPLIED/STORAGE AND HANDLING (16.1)]

The concomitant use of Lazanda with CYP3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression [see DRUG INTERACTIONS (7)].

MEDICATION ERRORS

Substantial differences exist in the pharmacokinetic profile of Lazanda compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl that could result in fatal overdose.

When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to Lazanda. (2.1) When dispensing, do not substitute a Lazanda prescription for other fentanyl products. ABUSE POTENTIAL

Lazanda contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. Lazanda can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Lazanda in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Because of the risk for misuse, abuse, addiction, and overdose, Lazanda is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program.

Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyl transdermal system if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS, PEDIATRIC USE).

Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean half-life is approximately 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.

Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists.

All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. 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 transdermal system increased mean fentanyl AUC values by 120% and mean Cmax values by 61%.

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose should be adjusted if necessary.

Death and other serious medical problems have occurred when people were accidentally exposed to fentanyl transdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal system from an adult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while the caregiver was applying or removing the patch.

Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.

Misuse, Abuse and Diversion of Opioids Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when prescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Fentanyl transdermal system has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION).

Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Hypoventilation (Respiratory Depression) Serious or life-threatening hypoventilation may occur at any time during the use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy and following increases in dose.

Because significant amounts of fentanyl continue to be absorbed from the skin for 17 hours or more after the patch is removed, hypoventilation may persist beyond the removal of fentanyl transdermal system. Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized.

The use of concomitant CNS active drugs requires special patient care and observation.

Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl transdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Chronic Pulmonary Disease Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl transdermal system should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.

Head Injuries and Increased Intracranial Pressure Fentanyl transdermal system should not be used 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. Opioids may obscure the clinical course of patients with head injury. Fentanyl transdermal system should be used with caution in patients with brain tumors.

Interactions with Other CNS Depressants The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

Interactions with Alcohol and Drugs of Abuse Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Interactions with CYP3A4 Inhibitors The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted

Adverse Reactions

Clinical Trials Experience

Although fentanyl transdermal system use in post-operative or acute pain and in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system was originally evaluated in 357 post-operative adult patients for 1 to 3 days and 153 cancer patients for a total of 510 patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year.

Hypoventilation was the most serious adverse reaction observed in 13 (4%) post-operative patients and in 3 (2%) of the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.

Various adverse events were reported; a causal relationship to fentanyl transdermal system was not always determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who received fentanyl transdermal system. There has been no attempt to correct for a placebo effect, concomitant use of other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials.

Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in TABLE 1; similar reactions were seen in the 357 post-operative patients.

In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ≤ 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.

There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in children as young as 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), and nausea (24%).

Adverse events reported in pediatric patients at a rate of ≥1% are presented in TABLE 1.

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The following adverse effects have been reported in less than 1% of the 510 adult post-operative and cancer patients studied: Cardiovascular: bradycardia Digestive: abdominal distention Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility Respiratory: stertorous breathing, asthma, respiratory disorder Skin and Appendages, General: exfoliative dermatitis, pustules Special Senses: amblyopia Urogenital: bladder pain, oliguria, urinary frequency

Postmarketing Experience

The following adverse reactions have been reported in association with the use of fentanyl transdermal system and not reported in the pre-marketing adverse reactions section above: Body as a Whole: edema Cardiovascular: tachycardia Metabolic and Nutritional: weight loss Special Senses: blurred vision Urogenital: decreased libido, anorgasmia, ejaculatory difficulty

Drug Interactions

Agents Affecting Cytochrome P450 3A4 Isoenzyme System

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when fentanyl transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadminstration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING; CLINICAL PHARMACOLOGY, DRUG INTERACTIONS; WARNINGS and DOSAGE AND ADMINISTRATION for further information).

Central Nervous System Depressants

The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

MAO Inhibitors

Fentanyl transdermal system is not recommended for use in patients who have received MAOI within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.

The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 mcg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.

Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fentanyl (transdermal) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Fentanyl (transdermal) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Fentanyl (transdermal) in women who are nursing.

Pediatric Use

The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/hr and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. Approximately 90% of the total daily opioid requirement (fentanyl transdermal system plus rescue medication) was provided by fentanyl transdermal system.

Geriatic Use

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the fentanyl transdermal system in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance

Gender

There is no FDA guidance on the use of Fentanyl (transdermal) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Fentanyl (transdermal) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Fentanyl (transdermal) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Fentanyl (transdermal) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Fentanyl (transdermal) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Fentanyl (transdermal) in patients who are immunocompromised.

Administration and Monitoring

Administration

Transdermal

Monitoring

There is limited information regarding Fentanyl (transdermal) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Fentanyl (transdermal) and IV administrations.

Overdosage

Clinical Presentation The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most serious significant effect being hypoventilation.

Treatment For the management of hypoventilation, immediate countermeasures include removing the fentanyl transdermal system and physically or verbally stimulating the patient. These actions can be followed by administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following an overdose may be longer than the effects of the narcotic antagonist’s action (the half-life of naloxone ranges from 30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibility of re-narcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and the release of catecholamines.

Always ensure a patent airway is established and maintained, administer oxygen and assist or control respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body temperature and fluid intake should be maintained.

If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy.

Pharmacology

There is limited information regarding Fentanyl (transdermal) Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Fentanyl (transdermal) Mechanism of Action in the drug label.

Structure

There is limited information regarding Fentanyl (transdermal) Structure in the drug label.

Pharmacodynamics

Because of the risk for serious or life-threatening hypoventilation, fentanyl transdermal system is CONTRAINDICATED in the treatment of post-operative and acute pain and in patients who are not opioid-tolerant. In clinical trials of 357 patients with acute pain treated with fentanyl transdermal system, 13 patients experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in patients weighing less than 63 kg (9 of 13). Although patients with impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naive post-operative patients who have experienced clinically significant hypoventilation and death with fentanyl transdermal system.

While most patients using fentanyl transdermal system chronically develop tolerance to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during therapy.

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive usual doses of opioids or other CNS drugs associated with hypoventilation in addition to fentanyl transdermal system. The use of fentanyl transdermal system is contraindicated in patients who are not tolerant to opioid therapy.

The use of fentanyl transdermal system should be monitored by clinical evaluation, especially within the initial 24 to 72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older.

Pharmacokinetics

Fentanyl transdermal system is a drug-in-adhesive matrix designed formulation. Fentanyl is released from the matrix at a nearly constant amount per unit time. The concentration gradient existing between the matrix and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the copolymer release membrane and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.

While there is variation in dose delivered among patients, the nominal flux of the systems (25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient.

Following fentanyl transdermal system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial fentanyl transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Peak serum concentrations of fentanyl generally occurred between 24 and 72 hours after initial application (see TABLE A). Serum fentanyl concentrations achieved are proportional to the fentanyl transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first two system applications. By the end of 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. Patients reach and maintain a steady-state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl.

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Nonclinical Toxicology

There is limited information regarding Fentanyl (transdermal) Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Fentanyl (transdermal) Clinical Studies in the drug label.

How Supplied

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Safety and Handling Fentanyl transdermal system is supplied in sealed transdermal systems which pose little risk of exposure to healthcare workers. Do not use a fentanyl transdermal system if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

KEEP FENTANYL TRANSDERMAL SYSTEM OUT OF THE REACH OF CHILDREN AND PETS.

Storage

Store in original unopened pouch. Store up to 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Apply immediately after removal from individually sealed pouch. Do not use if the pouch seal is broken. For transdermal use only.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Fentanyl (transdermal) Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Fentanyl (transdermal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • FENTANYL TRANSDERMAL SYSTEM[1]

Look-Alike Drug Names

There is limited information regarding Fentanyl (transdermal) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ "FENTANYL TRANSDERMAL SYSTEM- fentanyl patch, extended release".
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