WARNINGS
IONSYS™ should be prescribed only by persons knowledgeable in the administration of potent opioids and in the management of patients receiving potent opioids for treatment of pain. Patients treated with IONSYS™ should be under the supervision of medical personnel with expertise in the detection and management of hypoventilation, including airway management and the use of opioid antagonists.
Inappropriate use of IONSYS™, leading to ingestion or contact with mucous membranes, or unintended exposure to the fentanyl hydrogel, could lead to the absorption of a potentially fatal dose of fentanyl. Therefore, the hydrogels should not come into contact with fingers or mouth.
The mean terminal elimination half-life of IONSYS™ is 11 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require continued monitoring after IONSYS™ removal since serum fentanyl concentrations decline gradually (See Figure 1B).
To avoid potential overdosing, only the patient should activate IONSYS™. IONSYS™ should be used only in hospitals, by patients under medical supervision and direction. More than one IONSYS™ system should not be applied to a patient at the same time.
If the fentanyl hydrogel becomes separated from the IONSYS™ system, contact can be harmful to humans and animals. If the hydrogel becomes separated from the IONSYS™ system during removal, use gloves or tweezers to remove the hydrogel from the skin and properly dispose of in accordance with state and federal regulations for controlled substances. The skin area that had been in contact with the hydrogel should be thoroughly flushed with water. Do not use soap, alcohol, or other solvents to remove the hydrogel as they may enhance the drug's ability to penetrate the skin. In the event that the IONSYS™ system falls off, ensure that the entire IONSYS™ system (i.e. with hydrogel) is collected and properly disposed of.
Prior to discharge from the hospital, medical personnel must remove the IONSYS™ system and dispose of it properly (see DOSAGE AND ADMINISTRATION, Disposal). After the maximum dosage administration, a significant amount of fentanyl remains in the device.
Misuse, Abuse and Diversion of Opioids
Fentanyl is an opioid agonist of the morphine type. Opioid agonists 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 opioid agonists, legal or illicit. This should be considered when prescribing or dispensing IONSYS™ in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
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.
Interactions with Alcohol and Drugs of Abuse
Fentanyl may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
PRECAUTIONS
General
Only patients who are able to understand and follow the instructions to operate IONSYS™ should use the system.
Patients should be titrated to an acceptable level of analgesia before initiating dosing with the IONSYS™ system.
IONSYS™ should be applied to intact, non-irritated, and non-irradiated skin on the chest or upper outer arm. Care should be taken to avoid exposing IONSYS™ to water as this could cause the system to fall off or stop working.
The error detection circuitry in IONSYS™ uses a series of audible signals to alert the patient or caregiver when a dose is not being delivered in response to the patient's attempt to activate a dose. Therefore, IONSYS™ should be used with caution in patients who have high frequency hearing impairment (see DOSAGE AND ADMINISTRATION, Troubleshooting). The testing instructions in the Dosage and Administration section can be used to demonstrate the audible tone for patients if there is any question of the patient's ability to hear the tone.
IONSYS™ contains metal parts and should be removed before an MRI procedure, cardioversion, or defibrillation to avoid damage to the system from the strong electromagnetic fields set up by these procedures. (See DOSAGE AND ADMINISTRATION, Disposal). IONSYS™ contains radio-opaque components and may interfere with an X-ray image or CAT scan. The low-level electrical current provided by IONSYS™ does not result in electromagnetic interference with other electromechanical devices like pacemakers or electrical monitoring equipment.
Interactions with other CNS Depressants
The concomitant use of other central nervous system depressants, including other opioids, sedatives, hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, or alcoholic beverages, may produce additive depressant effects. Hypoventilation, hypotension, profound sedation, respiratory depression, coma, or death may result. Therefore, the use of concomitant CNS depressants requires individual adjustment of dosage of the concomitant medication and close observation of the patient.
As with other opioid medications, IONSYS™ may impair the mental and/or physical ability required for the performance of potentially hazardous tasks.
Chronic Opioid Therapy
IONSYS™ has not been studied in the treatment of breakthrough pain in patients on chronic opioid therapy and is not recommended for this purpose.
Patients on chronic opioid therapy or with a history of opioid abuse may require higher analgesic doses in the post-operative period than are available from IONSYS™; therefore these patients should be evaluated frequently to ensure they are receiving adequate analgesia.
Topical Skin Reactions
Topical skin reactions (erythema, sweating, vesicles, papules/pustules) may occur after removal of IONSYS™ and are typically limited to the application site area. Reactions typically resolve without treatment. If a severe skin reaction is observed, treat with a topical antiseptic/antibiotic as appropriate.
Respiratory Depression
Fentanyl may cause potentially life-threatening respiratory depression. 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 (see WARNINGS).
Pulmonary Disease
Because potent opioids may cause serious or life-threatening hypoventilation, IONSYS™ should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure
IONSYS™ 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. IONSYS™ should be used with caution in patients with brain tumors.
Cardiac Disease
Fentanyl may produce bradycardia in some patients. Therefore, IONSYS™ should be administered with caution to patients with bradyarrhythmias.
Hepatic Disease
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, IONSYS™ should be used with caution in these patients.
Renal Disease
Approximately 10% of administered fentanyl is excreted unchanged by the kidney. Insufficient data are available on the use of IONSYSTM in patients with impaired renal function. IONSYS™ should be used with caution in these patients.
Patient Information
A Patient Instructions for Use sheet is included in the package for IONSYS™ (see Patient Bedside Information Sheet). Health care professionals are encouraged to review this material with patients.
- Patients should be advised not to let anyone else activate the dosing button on the IONSYS™ system 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.
- Patients should be instructed not to touch the sticky side of the system and not to touch the gels. Patients should be cautioned that fentanyl is rapidly absorbed by the eyes and mouth, and could be harmful or fatal if absorbed this way. Patients should be advised 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.
- Patients should be advised to inform the health care provider of any allergies to fentanyl, cetylpiridinium chloride (e.g. Cepacol ® ), or any components of the IONSYS™ system.
- Patients should be advised not to give IONSYS™ to other people, as it may lead to serious and life-threatening events.
Drug Interactions
Central Nervous System Depressants
The concomitant use of other central nervous system depressants, including other opioids, sedatives, hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, or alcoholic beverages, may produce additive depressant effects. Hypoventilation, hypotension, profound sedation, coma, or death may occur. Therefore, use of concomitant CNS depressants requires individual adjustment of dosage of the concomitant medication and observation of a given patient.
Agents Affecting CYP3A4 Isoenzyme System
Fentanyl is metabolized mainly via the cytochrome P450 3A4 enzyme (CYP3A4). Therefore, drug interactions may occur when IONSYS™ is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity, such as rifampin, carbamazepine, phenytoin, and Saint John's Wort may cause increased clearance of fentanyl and reduce the efficacy of IONSYS™. The concomitant use of fentanyl with CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g. ritonavir) may result in a decrease in fentanyl clearance, which could increase or prolong adverse drug effects including serious respiratory depression. In this situation, special patient care and observation are appropriate.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Studies in animals to evaluate the carcinogenic potential of fentanyl HCl have not been conducted. There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays.
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 (0, 0.025, 0.1 or 0.4 mg/kg/day) 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 (0, 0.025, 0.1 or 0.4 mg/kg/day) 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 human dose for a period of 12 days.
Pregnancy
Teratogenic Effects—Pregnancy Category C
No epidemiologic 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 1.5 times the maximum available daily human dose 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 maximum achievable human daily dose on a mg/m2 basis).
There are no adequate and well-controlled studies in pregnant women. IONSYS™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy 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 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 day 28 which recovered by day 50). The mid-dose and the high-dose are 0.3 and 1.5 times the maximum available daily human dose on a mg/m2 basis.
Labor and Delivery
Fentanyl readily passes across the placenta to the fetus; therefore IONSYS™ is not recommended for analgesia during labor and delivery.
Nursing Mothers
Fentanyl is excreted in human milk; therefore IONSYS™ is not recommended for use in nursing women because of the possibility of sedation and/or respiratory depression in their infants.
Pediatric Use
Not for pediatric use. The efficacy and safety of IONSYS™ have not been adequately studied in pediatric patients under 18 years of age.
Preliminary pediatric studies using iontophoretically-delivered fentanyl at a lower dose suggested that pediatric patients were more vulnerable to application site reactions, which were more severe than in adults.
Geriatric Use
IONSYS™ 40 mcg has been studied in 499 patients 65 years or older; 174 of whom were 75 years or older. No overall 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 (see PRECAUTIONS).
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