"Young children have died or become seriously ill from accidental exposure to a skin patch containing fentanyl, a powerful pain reliever. As a result of this, the Food and Drug Administration (FDA) is issuing a Drug Safety Communication to warn pa"...
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Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including fentanyl, even when used as recommended. Respiratory depression from opioid use, including fentanyl, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
Keep IONSYS out of reach of children at all times.
Accidental exposure to an intact IONSYS or to its components, through contact with skin or mucous membranes can result in a fatal overdose of fentanyl. Following accidental contact with IONSYS or its components, immediately rinse the affected area thoroughly with water. Do not use soap, alcohol, or other solvent because they may enhance the drug's ability to penetrate the skin. The individual exposed should be monitored for signs of respiratory or central nervous system depression.
If IONSYS is not handled correctly using gloves healthcare professionals are at risk of accidental exposure to a fatal overdose of fentanyl.
IONSYS is for hospital use only. Use of IONSYS outside of the hospital setting can lead to accidental exposure in others for whom it is not prescribed, causing fatal respiratory depression. Prior to the patient leaving the hospital, medical personnel must remove IONSYS and dispose of it properly.
IONSYS Risk Evaluation And Mitigation Strategy (REMS) Program
IONSYS is available only through a restricted program under a REMS called the IONSYS REMS Program because of the risk of respiratory depression resulting from accidental exposure [see Life-Threatening Respiratory Depression].
Notable requirements of the IONSYS REMS Program include the following:
- Healthcare facilities that dispense and administer IONSYS must be certified in the IONSYS REMS program and comply with the REMS requirements.
- Hospitals must only dispense IONSYS for hospital use.
Further information about the IONSYS REMS Program is available at www.ionsysrems.com, or by calling 1-877-488-6835.
Addiction, Abuse, And Misuse
IONSYS contains fentanyl, an opioid agonist and a Schedule II controlled substance. Fentanyl can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing IONSYS in situations where the physician or pharmacist is concerned about an increased risk of addiction, abuse, and misuse. Concerns about addiction, abuse, and misuse, however, should not prevent the proper management of pain.
Assess each patient's risk for opioid abuse or addiction prior to prescribing IONSYS. The risk for opioid abuse is increased in patients 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 opioids; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.
Contact local State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions With Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression, and death may result if IONSYS is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of IONSYS in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression [see DRUG INTERACTIONS].
Risk Of Injury During Magnetic Resonance Imaging (MRI) Procedure
The IONSYS device is considered MR Unsafe. IONSYS contains metal parts and must be removed and properly disposed of before an MRI procedure to avoid injury to the patient and damage to IONSYS. It is unknown if exposure to an MRI procedure increases release of fentanyl from IONSYS. Monitor any patients wearing IONSYS with inadvertent exposure to an MRI for signs of central nervous system and respiratory depression.
Risk Of IONSYS Use During Other Procedures Or Near Certain Equipment
Cardioversion, Defibrillation, Radiographic Imaging Procedures other than MRI, or Diathermy
Use of IONSYS during cardioversion, defibrillation, X-ray, CT, or diathermy can damage IONSYS from the strong electromagnetic fields set up by these procedures. IONSYS contains radio-opaque components and may interfere with an X-ray image or CT scan. Remove and properly dispose of IONSYS prior to cardioversion, defibrillation, X-ray, CT, or diathermy [see DOSAGE AND ADMINISTRATION].
Synthetic Materials and Electronic Security Systems
Avoid contact with synthetic materials (such as carpeted flooring) to reduce the possibility of electrostatic discharge and damage to IONSYS. Avoid exposing IONSYS to electronic security systems to reduce the possibility of damage to IONSYS. See IONSYS Important Device Instructions for additional details.
Communications Equipment and Radio Frequency Identification Transmitters
Use of IONSYS near communications equipment (e.g., base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast and TV broadcast Radio) and Radio Frequency Identification (RFID) transmitters can damage IONSYS. Depending on the rated maximum output power and frequency of the transmitter, the recommended separation distance between IONSYS and communications equipment or the RFID transmitter ranges between 0.12 and 23 meters. See IONSYS Important Device Instructions for detailed instructions regarding recommended separation distances.
Other Electromechanical Devices Including Pacemakers or Electrical Monitoring Equipment The low-level electrical current provided by IONSYS does not result in electromagnetic interference with other electromechanical devices like pacemakers or electrical monitoring equipment.
If exposure to the procedures listed above, electronic security systems, electrostatic discharge, communications equipment, or RFID transmitters occurs, and if IONSYS does not appear to function normally [see DOSAGE AND ADMINISTRATION], remove IONSYS and replace with a new IONSYS. See IONSYS Important Device Instructions for additional details including information on troubleshooting device malfunction and electromagnetic compatibility.
Topical Skin Reactions
Topical skin reactions (erythema, sweating, vesicles, papules/pustules) may occur with use of IONSYS and are typically limited to the application site area. If a severe skin reaction is observed, remove IONSYS and discontinue further use.
Use In Elderly, Cachectic, And Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely; especially when IONSYS is used concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression].
Use In Patients With Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy with IONSYS, as in these patients, even usual therapeutic doses of IONSYS may decrease respiratory drive to the point of apnea [see Life-Threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in these patients if possible.
IONSYS may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see DRUG INTERACTIONS]. Monitor these patients for signs of hypotension after initiating IONSYS. Avoid the use of IONSYS in patients with circulatory shock as IONSYS may cause vasodilation that can further reduce cardiac output and blood pressure.
Use In Patients With Head Injury Or Increased Intracranial Pressure
IONSYS is not suitable for use in patients who are not alert and able to follow directions. Monitor patients using IONSYS who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with IONSYS. IONSYS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids, including IONSYS, may also obscure the clinical course in a patient with a head injury.
Avoid the use of IONSYS in patients with impaired consciousness or coma.
Use In Patients With Gastrointestinal Conditions
IONSYS is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. Fentanyl may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Opioids, including IONSYS, may cause increases in serum amylase.
Use In Patients With Convulsive Or Seizure Disorders
IONSYS may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during IONSYS therapy.
IONSYS may produce bradycardia in some patients. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with IONSYS.
Cytochrome P450 3A4 Inhibitors And Inducers
Since the CYP3A4 isoenzyme plays a major role in the metabolism of fentanyl, drugs that alter CYP3A4 activity may cause changes in clearance of fentanyl which could lead to changes in fentanyl plasma concentrations.
The concomitant use of IONSYS with a CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, 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. Carefully monitor patients receiving IONSYS and any CYP3A4 inhibitor for signs of sedation and respiratory depression for an extended period of time, and make dosage adjustments as needed.
If co-administration is necessary, caution is advised when initiating IONSYS treatment in patients currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Insufficient data are available on the use of IONSYS in patients with impaired hepatic function. Since fentanyl is eliminated by hepatic metabolism and fentanyl clearance may decrease in patients with hepatic disease, monitor patients with hepatic impairment for signs of sedation and respiratory depression [see Use In Specific Populations and CLINICAL PHARMACOLOGY].
A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Monitor for signs of sedation and respiratory depression in patients with renal impairment [see Use in Specific Populations and CLINICAL PHARMACOLOGY].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (IONSYS Guide for Patients).
Life-Threatening Respiratory Depression
- Discuss the risk of respiratory depression with patients, explaining that the risk is greatest when starting IONSYS. Advise patients how to recognize respiratory depression and to seek medical attention if they are experiencing breathing difficulties.
- Advise patients not to leave the hospital with an IONSYS [see WARNINGS AND PRECAUTIONS].
- Advise patients not to let anyone else activate the dosing button on the IONSYS since only the patient knows how much pain he or she is experiencing. Patients should be cautioned that allowing others to activate the device may result in a potentially fatal overdose [see DOSAGE AND ADMINISTRATION].
- Advise patients not to give IONSYS to other people, as it may lead to a fatal overdose of fentanyl.
- Advise patients not to let anyone touch IONSYS if it falls off accidentally and to contact their nurse, pharmacist, or doctor immediately. Accidental exposure to the fentanyl hydrogel may result in a fatal overdose of fentanyl.
- Instruct patients not to remove or reposition IONSYS and that IONSYS must be removed only by medical personnel [see WARNINGS AND PRECAUTIONS].
- Instruct patients not to touch the sticky side of IONSYS and not to touch the gels. Caution patients that fentanyl is rapidly absorbed by the eyes and mouth and could be harmful or fatal if absorbed this way. Advise patients to inform a health care provider if accidental exposure occurs and to immediately rinse the affected area with copious amounts of water. Soap, alcohol, or other solvents should not be used because they may enhance permeability [see WARNINGS AND PRECAUTIONS].
- Instruct patients to keep IONSYS out of the reach of children at all times [see WARNINGS AND PRECAUTIONS].
Addiction, Abuse and Misuse
- Inform patients that the use of IONSYS, even when taken as recommended can result in addiction, abuse and misuse, which can lead to overdose and death [see WARNINGS AND PRECAUTIONS].
- Advise patients to inform the health care provider of any allergies to fentanyl, cetylpiridinium chloride (e.g., Cepacol®), or any components of IONSYS.
- Advise patients that the level of current (62 microA/cm²) provided by IONSYS is generally imperceptible to the patient.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 0.033 mg/kg/day in males or 0.1 mg/kg/day in females. These lifetime doses in rats are approximately 0.1 and 0.3, respectively, the maximum recommended human dose (MRHD) of 3.2 mg/day by transdermal administration based on a mg/m² body surface area comparison and a 60 kg human body weight.
Fentanyl is not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay), the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the in vitro chromosomal aberration assays using either human lymphocytes or Chinese hamster ovary cells.
Impairment of Fertility
The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl doses of 0, 0.025, 0.1, or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2 times, respectively, the MHRD) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl doses of 0, 0.025, 0.1, or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2 times, respectively, the MHRD) via continuous intravenous infusion for 14 days prior to mating until Day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.2 times the maximum available daily human dose on a mg/m² basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the MRHD for a period of 12 days.
Use In Specific Populations
There are no studies with the use of IONSYS in pregnant women. Limited published data on fentanyl use during pregnancy are insufficient to establish any drug-associated risks. In animal reproduction and developmental studies, at doses within the dosing range of humans, there was an increased risk for early embryonic lethality, decreased pup survival, and delays in developmental landmarks of surviving pups [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. IONSYS is not recommended for use in women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including IONSYS, can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Neonates, whose mothers received opioid analgesics during labor, must be observed closely for signs of respiratory depression. An opioid antagonist, such as naloxone, must be available for reversal of narcotic-opioid induced respiratory depression in the neonate.
The potential effects of fentanyl on embryo-fetal development were studied in rat and rabbit models.
Published literature reports that administration of fentanyl (0, 0.01, 0.1, or 0.5 mg/kg/day) to pregnant female Sprague-Dawley rats from Gestation Day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity. The high dose is approximately 1.5 times the daily maximum recommended human dose (MRHD) of 3.2 mg/day based on a mg/m² body surface area basis and a 60 kg human body weight.
In contrast, the intravenous administration of fentanyl at doses of 0, 0.01, or 0.03 mg/kg (equivalent to 0.03 and 0.09 times, respectively, the MHRD) to pregnant female rats from Gestation Day 6 to 18 resulted in evidence of embryo toxicity 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 Gestation Day 6 to 18. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity (decreased body weight and sedation). 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 (2.4 times the MRHD).
The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Pregnant female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion (equivalent to 0.08, 0.3, and 1.2 times, respectively, the MRHD) from Gestation Day 6 through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at Post-Natal Day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at Post-Natal Day 28 which recovered by Post-Natal Day 50). No adverse effects were observed at 0.08 times the MRHD.
Limited published literature reports that fentanyl is present in human milk at low levels, which resulted in an estimated infant dose of 0.38% of the maternal weight-adjusted dosage. There are no reports of adverse effects on the breastfed infant and no information on the effects on milk production. The developmental and health benefits from breastfeeding should be considered along with the mother's need for IONSYS and any potential effects on the breastfed infant from IONSYS or from the underlying maternal condition.
The efficacy and safety of IONSYS have not been established in pediatric patients under 18 years of age.
IONSYS 40 mcg has been studied in 499 patients 65 years or older; 174 of whom were 75 years or older. No major differences in safety or effectiveness were observed between these subjects and younger subjects. However, the incidence of the following events was slightly higher ( ≥ 1%) in patients ≥ 65 years compared with patients who were 18 to 64 years of age: hypotension (4% versus 3%), confusion (2% versus < 1%), hypokalemia (3% versus 1%), hypoxia (3% versus 2%), and hypoventilation (2% versus < 1%).
In a pharmacokinetic study of IONSYS conducted in 63 healthy volunteers (25 subjects older than 65 years), age did not significantly affect the extent of drug absorption. Literature suggests that the clearance of fentanyl may be reduced and the terminal half-life prolonged in the elderly.
Monitor geriatric patients closely for signs of sedation and respiratory depression, particularly when initiating therapy with IONSYS and when given in conjunction with other drugs that depress respiration [see WARNINGS AND PRECAUTIONS].
Insufficient data are available on the use of IONSYS in patients with impaired hepatic function. Since fentanyl is eliminated by hepatic metabolism and fentanyl clearance may decrease in patients with hepatic disease, monitor patients with hepatic impairment closely for signs of central nervous system and respiratory depression, especially when initiating treatment with IONSYS.
Approximately 10% of administered fentanyl is excreted unchanged by the kidney. Insufficient data are available on the use of IONSYS in patients with impaired renal function to determine effects on renal clearance of fentanyl. Monitor patients with renal impairment closely for signs of central nervous system and respiratory depression, especially when initiating treatment with IONSYS.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/8/2015
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