Data from FDA - Curated by EPG Health - Last updated 08 May 2018

Indication(s)

1. INDICATIONS AND USAGE IONSYS is indicated for the short-term management of acute postoperative pain severe enough to require an opioid analgesic in the hospital and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions ( 5.3)] , reserve IONSYS for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia. IONSYS is: Only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use. Not for home use. IONSYS is for use only in patients in the hospital. Discontinue treatment with IONSYS before patients leave the hospital. For use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics. IONSYS contains fentanyl, an opioid agonist. IONSYS is indicated for the short-term management of acute postoperative pain severe enough to require an opioid analgesic in the hospital and for which alternative treatments are inadequate. ( 1) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve IONSYS for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]: Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia IONSYS is: Only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use. ( 1) Not for home use. IONSYS is for use only in patients in the hospital. Discontinue treatment with IONSYS before patients leave the hospital. ( 1) For use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics. ( 1)

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Advisory information

contraindications
4. CONTRAINDICATIONS IONSYS is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.1)] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.1)] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.13)] Hypersensitivity to fentanyl, cetylpyridinium chloride (e.g., Cepacol®), or any components of IONSYS [see Adverse Reactions ( 6.1, 6.2)]. Significant respiratory depression. ( 4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4) Hypersensitivity to fentanyl, cetylpyridinium chloride (e.g., Cepacol ®), or any components of IONSYS. ( 4)
Adverse reactions
6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Life-Threatening respiratory Depression [see Warnings and Precautions ( 5.1)] Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.3)] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.5)] Serotonin Syndrome [see Warnings and Precautions ( 5.9)] Adrenal Insufficiency [see Warnings and Precautions ( 5.10)] Severe Hypotension [see Warnings and Precautions ( 5.11)] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.13)] Seizures [see Warnings and Precautions ( 5.14)] Withdrawal [see Warnings and Precautions ( 5.17)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.20)] Most common adverse reactions (frequency ≥ 2%) were headache, hypotension, nausea, vomiting, anemia, dizziness, application site reaction-erythema, pruritus, and urinary retention. ( 6) To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-877-488-6835 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled and uncontrolled studies, the safety of IONSYS 40 mcg was evaluated in a total of 2114 patients with acute postoperative pain requiring opioid analgesia. The most common adverse reactions (≥ 2%) in the placebo-controlled studies, regardless of relationship to study medication, are listed in Table 1. Table 1: Adverse Reactions with Incidence ≥ 2% in Placebo-controlled Studies 1, 2, and 3 (N=791; 24 Hour Duration) Adverse Reactions IONSYS (n=475) Placebo (n=316) Body as a Whole Headache 9% 7% Cardiovascular System Hypotension 2% <1% Digestive System Nausea 39% 22% Vomiting 12% 6% Hemic and Lymphatic System Anemia 3% <1% Nervous System Dizziness 3% 1% Skin System Application site reaction- Erythema 14% 2% Pruritus 6% <1% Urogenital System Urinary retention 3% <1% NOTE: Patients reported as having "Nausea and vomiting" are included in "Nausea" and "Vomiting" in Table 1. Other Adverse Reactions Other adverse reactions that were reported (excluding adverse reactions listed in Table 1) in 4 active comparator trials vs. IV PCA morphine in patients treated with IONSYS (n=1288) are described below: Body as a Whole: abdominal pain, back pain, extremity pain, chest pain, chills, abdomen enlarged, asthenia, abscess, hypothermia Cardiovascular System: syncope, postural hypotension, vasodilation, hypertension, atrial fibrillation, bradycardia, tachycardia, bigeminy, arrhythmia, myocardial infarct Digestive System: constipation, flatulence, dyspepsia, ileus, dry mouth, diarrhea Metabolic and Nutritional System: peripheral edema, healing abnormal, edema, dehydration Musculoskeletal System: leg cramps and myalgia Nervous System : insomnia, anxiety, somnolence, confusion, paresthesia, hypesthesia, nervousness, agitation, abnormal dreams, tremor Respiratory System: hypoxia, hypoventilation, dyspnea, apnea, cough increased, asthma, hiccup, atelectasis, rhinitis, hyperventilation Skin System: application site reactions including: itching, vesicles, papules/pustules, edema, pain, burning, dry and flaky skin, and vesiculobullous rash, wound site oozing/bleeding, wound site inflammation/erythema, rash, sweating Special Senses: abnormal vision-blurred vision Urogenital System: urination impaired, hematuria, urinary tract infection, urinary urgency, dysuria Scheduled observation of the skin approximately 24 hours after IONSYS removal was included in several studies. Some redness at the skin sites was observed in approximately 60% of patients at this observation. The skin findings included erythema, edema, and papules. The majority of these events were categorized as mild. Two patients were noted to have hyperpigmentation lasting 2-3 weeks at the application site. Three patients noted a rectangular mark at the application site, which persisted for up to 3 months after study completion. 6.2 Post Marketing Experience The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most commonly observed events were related to application site reactions which included urticaria, application site discharge, erosion, hyperesthesia, pustules, rash and scab, application site bleeding, application site infection, and necrosis. Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in IONSYS. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)].

Usage information

Dosing and administration
2. DOSAGE AND ADMINISTRATION Do not use more than one IONSYS at a time. ( 2.1) Patients should be titrated to comfort before initiating IONSYS. ( 2.2) For transdermal use only. Apply one IONSYS to intact, non-irritated, and non-irradiated skin on the chest or upper outer arm. ( 2.2, 2.3) Each IONSYS operates up to 24 hours or 80 doses, whichever comes first. IONSYS may be used for a maximum of 72 hours of therapy for acute postoperative pain, with each subsequent IONSYS applied to a different skin site. ( 2.2, 2.3 ) See full prescribing information for detailed instructions concerning administration, disposal and discontinuation of IONSYS. ( 2.3, 2.4, 2.5, 2.6 ) See IONSYS Important Device Instructions for additional details including troubleshooting device malfunction. Do not stop IONSYS abruptly in a physically dependent patient. ( 2.5) 2.1 Important Administration Instructions IONSYS IS FOR HOSPITAL USE ONLY BY PATIENTS UNDER MEDICAL SUPERVISION AND DIRECTION. PRIOR TO THE PATIENT LEAVING THE HOSPITAL, MEDICAL PERSONNEL MUST REMOVE IONSYS AND DISPOSE OF IT PROPERLY [see Dosage and Administration ( 2.3, 2.4)]. ONLY THE PATIENT MAY ACTIVATE IONSYS. ONLY ONE IONSYS MAY BE APPLIED AT A TIME. If inadequate analgesia is achieved with one IONSYS, either provide additional supplemental analgesic medication or replace with an alternate analgesic medication. 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 close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10)]. Remove and properly dispose of IONSYS prior to MRI, cardioversion, defibrillation, or diathermy [see Warnings and Precautions ( 5.6, 5.7)]. To reduce the risk for shock, avoid contact with synthetic materials (such as carpeted flooring) while assembling IONSYS and avoid exposing IONSYS to electronic security systems [see Warnings and Precautions ( 5.7)]. Depending on the rated maximum output power and frequency of the transmitter, the recommended separation distance between IONSYS and communications equipment or a Radio Frequency Identification (RFID) transmitter ranges between 0.12 and 23 meters [see Warnings and Precautions ( 5.7)]. See IONSYS Important Device Instructions for additional details, including information on troubleshooting device malfunction, recommended separation distances, and electromagnetic compatibility 2.2 Dosage IONSYS (see Figure 1A) is for use only after patients have been titrated to an acceptable level of analgesia using another opioid analgesic. Apply one IONSYS to healthy, unbroken/intact, non-irritated, and non-irradiated skin on the chest or upper outer arm ONLY. IONSYS provides a 40 mcg dose of fentanyl per activation. It is important to instruct patients how to operate IONSYS to self-administer doses of fentanyl as needed to manage their acute, short-term, postoperative pain. Allow only the patient to self-administer doses of IONSYS. Each on-demand dose is delivered over a 10-minute period. To initiate administration of IONSYS, the patient must press and release the button twice within 3 seconds. One single audible beep indicates the start of delivery of each dose. The green light will start blinking rapidly and the digital display will alternate between a walking circle and the number of doses delivered. When the 10-minute dose is complete, the green light will blink at a slow rate and the display will show the number of doses delivered (see Figure 1B). Figure 1A: IONSYS Components Figure 1B: Assembled IONSYS A maximum of six 40-mcg doses per hour can be administered by IONSYS. The maximum amount of fentanyl that can be administered from a single IONSYS over 24 hours is 3.2 mg (eighty 40-mcg doses). Each IONSYS operates up to 24 hours or 80 doses, whichever comes first. Use one IONSYS at a time for up to 24 hours or 80 doses, whichever comes first. IONSYS may be used for a maximum of 3 days (72 hours) of therapy for acute postoperative pain, with each subsequent IONSYS applied to a different skin site [see Dosage and Administration ( 2.3)]. After the 24 hours have elapsed, or 80 doses have been delivered, IONSYS will not deliver any additional doses. The light and audible beep will not function. The digital display will continue to show the number of doses delivered for an additional 12 hours. If the patient tries to initiate a dose, IONSYS will ignore the dose request. Figure 1a Figure 1b 2.3 Administration of IONSYS For SINGLE-USE only: operates up to 24 hours or 80 doses, whichever comes first. FOR TRANSDERMAL USE ONLY Preparation of Patient Site 1. Choose healthy, unbroken skin on the upper outer arm or chest ONLY (see Figure 2). IONSYS may only be applied to one of the three sites shown in Figure 2. 2. Clip excessive hair if necessary. Do not shave as this may irritate skin. 3. Clean the site with alcohol and let it dry. Do not use soaps, lotions, or other agents. Assembly of IONSYS DO NOT USE IONSYS IF THE SEAL ON THE TRAY OR DRUG UNIT POUCH IS BROKEN OR DAMAGED. ALWAYS WEAR GLOVES WHEN HANDLING IONSYS. Complete these steps before applying IONSYS to the patient: Open the tray by peeling back the tray lid (see Figure 3a). Remove the foil (drug) pouch and the Controller. Open the pouch containing the Drug Unit starting at the pre-cut notch and then carefully tearing along the top of the pouch. Remove the Drug Unit from the pouch and place on a hard, flat surface. Align the matching shapes of the Controller and the Drug Unit (see Figure 3b). Press on both ends of the device to ensure that the snaps at both ends are fully engaged (see Figure 3c). You should hear one or two clicks when the snaps are fully engaged (see Figure 3d). Once assembled, the digital display of the Controller will complete a short self-test during which there will be one audible beep, the red light will blink once, and the digital display will flash the number “88”. At the end of the self-test, the display will show the number “0” and a green light will blink at a slow rate to indicate IONSYS is ready for application (see Figure 3e). Application of IONSYS ALWAYS WEAR GLOVES WHEN HANDLING IONSYS. Peel off and discard only the clear plastic liner covering the adhesive and hydrogels (see Figure 4a). Take care not to pull on the red tab while removing the clear plastic liner when preparing to apply IONSYS to the patient. The red tab is only to be used when separating IONSYS for disposal [see Dosage and Administration ( 2.4)]. Press and hold IONSYS firmly in place, with the sticky side down, onto patient’s skin for at least 15 seconds (see Figure 4b). Press with your fingers around the edges to be sure IONSYS adheres to the skin. Do not press the dosing button. Occasionally, IONSYS may loosen from the skin; if this occurs, secure it to patient’s skin by pressing the edges with fingers or securing with a non-allergenic tape to be sure that all edges make complete contact with the skin. If using tape, apply tape along the long edges to secure IONSYS to patient’s skin (see Figure 4c). Do not tape over the button, the light, or the digital display. Do not tape if evidence of blistered or broken skin. After taping, if IONSYS beeps again, remove and dispose. Place a new IONSYS on a different skin site. Each IONSYS may be used for up to 24 hours from the time it is assembled or until 80 doses have been administered, whichever comes first. Operation of IONSYS A recessed button is located on the top housing of IONSYS. To initiate administration of a fentanyl dose, the patient must press and release the button twice within 3 seconds. IONSYS should only be activated by the patient. One single audible beep indicates the start of delivery of each dose. The green light will start blinking rapidly and the digital display will alternate between a walking circle (see Figure 5) and the number of doses delivered. Each dose will be delivered over 10-minutes. During this time IONSYS is locked-out and will not respond to additional button presses. When the 10-minute dose is complete, the green light will return to a slow rate of blinking and the display will show the number of doses delivered. IONSYS is now ready to be used again by the patient. The next dose cannot begin until the previous 10‑minute delivery cycle is complete. Pressing the button during delivery of a dose will not result in additional drug being administered. A healthcare professional must observe the first dose administered to ensure that the patient understands how to operate IONSYS and that IONSYS is working properly. Each IONSYS will cease functioning at the end of 24 hours of use, or after 80 doses have been administered, whichever comes first. The green light will turn off and the number of doses delivered will flash on and off. The flashing digital display may be turned off by pressing and holding the dosing button for 6 seconds. See IONSYS Important Device Instructions for additional details, including information on troubleshooting device malfunction. Removal of IONSYS ALWAYS WEAR GLOVES WHEN HANDLING IONSYS. IONSYS may be removed at any time. However, once IONSYS has been removed, the same IONSYS must not be reapplied. At the end of 24 hours of use, or after 80 doses have been delivered, IONSYS will deactivate and should be removed from the patient’s skin. With gloves on, remove IONSYS from the patient (see Figure 6). IONSYS contains two hydrogels (see Figure 4a), one of which contains fentanyl [see Description ( 11.2)]. Ensure both hydrogels remain with the removed IONSYS. If the hydrogel becomes separated from IONSYS 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. If the patient requires additional analgesia a new IONSYS should be applied. In this case, IONSYS should be applied to a new skin site on the upper outer arm or chest. One of the hydrogels contains fentanyl; take care not to touch the exposed hydrogel compartments or the adhesive (see Figure 4a). If a hydrogel drug reservoir is touched accidentally, rinse the area thoroughly with water (do not use soap). Fig 2 Fig 3abcde image of removing liner Fig 4c Fig 5 Fig 6 2.4 Disposal of IONSYS ALWAYS WEAR GLOVES WHEN HANDLING IONSYS. Contact with the hydrogels contained in IONSYS can result in a fatal overdose of fentanyl. Handle the used IONSYS by the sides and top while avoiding contact with the hydrogel. Dispose of IONSYS in accordance with state and federal regulations for controlled substances. The used red bottom housing (see Figure 7a) of IONSYS contains a significant amount of fentanyl that could cause a fatal overdose of fentanyl. To dispose of a used IONSYS: With gloves on, pull the red tab to separate the red bottom housing containing fentanyl from IONSYS (see Figure 7a). Fold the red housing in half with the sticky side facing in (see Figure 7b). Dispose of the folded over red housing containing the residual fentanyl per the institution’s procedures for disposal of Schedule II drugs or by flushing it down the toilet. Hold down dosing button until the display goes blank and then dispose of the remaining part of IONSYS containing electronics in waste designated for batteries. Fig 7ab 2.5 Discontinuation of IONSYS To discontinue use of IONSYS, remove and dispose of IONSYS according to the preceding directions. Do not abruptly discontinue IONSYS in a physically-dependent patient [see Warnings and Precautions ( 5.17), Drug Abuse and Dependence ( 9.3)]. 2.6 Conversion from IONSYS to Alternate Analgesics Upon discontinuation of IONSYS, if upon evaluation, conversion to an alternate analgesic is required, titrate the dose of the new analgesic, based upon the patient’s report of pain, until adequate analgesia has been obtained, keeping in mind that the serum fentanyl concentration will decrease slowly following removal of IONSYS [see Clinical Pharmacology ( 12.3), Warnings and Precautions ( 5.1)]. During the period of converting analgesics, monitor the patient for signs of respiratory and central nervous system depression.
Use in special populations
8. USE IN SPECIFIC POPULATIONS Hepatic impairment and/or renal impairment: Monitor for signs of sedation and respiratory depression. ( 8.6, 8.7) 8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.20)]. Available data with IONSYS in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. 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]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.20)] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. IONSYS is not recommended for use in pregnant 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. Monitor neonates exposed to opioid analgesics during labor and respiratory depression. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data 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/m 2 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. 8.2 Lactation Risk Summary 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 clinical need for IONSYS and any potential effects on the breastfed infant from IONSYS or from the underlying maternal condition. Clinical Considerations Infants exposed to IONSYS through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast‑feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Clinical Pharmacology ( 12.2), Nonclinical Toxicology ( 13.1)]. 8.4 Pediatric Use The efficacy and safety of IONSYS have not been established in pediatric patients under 18 years of age. 8.5 Geriatric Use 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. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.1)] . Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Hepatic Impairment 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. 8.7 Renal Impairment 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.

Interactions

7. DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with IONSYS. Table 2: Clinically Significant Drug Interactions with IONSYS Inhibitors of CYP3A4 Clinical Impact: The concomitant use of IONSYS and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects [see Warnings and Precautions ( 5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology ( 12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl. Intervention: If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice. CYP3A4 Inducers Clinical Impact: The concomitant use of IONSYS and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology ( 12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions ( 5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology ( 12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.5)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.9]. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue IONSYS if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.9)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.1)]. Intervention: The use of IONSYS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of IONSYS and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when IONSYS is used concomitantly with anticholinergic drugs. Mixed Agonist/Antagonist and Partial Agonist Analgesics: Avoid use with IONSYS because they may reduce the analgesic effect of IONSYS or precipitate withdrawal. ( 7)

More information

Category Value
Authorisation number NDA021338
Agency product number 59H156XY46
Orphan designation No
Product NDC 65293-011
Date Last Revised 12-01-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1666837
Marketing authorisation holder The Medicines Company
Warnings WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; IONSYS REMS; ADDICTION, ABUSE, AND MISUSE; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Life-Threatening Respiratory Depression Serious, life‑threatening, or fatal respiratory depression may occur with use of IONSYS. Monitor for respiratory depression, especially during initiation of IONSYS [see Warnings and Precautions ( 5.1 )]. Only the patient should activate IONSYS dosing [see Dosage and Administration ( 2.1) and Warnings and Precautions ( 5.1)]. IONSYS Risk Evaluation and Mitigation Strategy (REMS) Program IONSYS is for use only in patients in the hospital. Discontinue treatment with IONSYS before patients leave the hospital [see Warnings and Precautions ( 5.1)]. Because of the risk of respiratory depression from accidental exposure, IONSYS is available through a restricted program called the IONSYS REMS Program. Healthcare facilities that dispense IONSYS must be certified in this program and comply with the REMS requirements [see Warnings and Precautions ( 5.2)]. Addiction, Abuse, and Misuse IONSYS exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions [see Warnings and Precautions ( 5.3)]. Cytochrome P450 3A4 Interaction The concomitant use of IONSYS with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving IONSYS and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.4), Drug Interactions ( 7), and Clinical Pharmacology ( 12.3)]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions ( 5.5), Drug Interactions ( 7)]. Reserve concomitant prescribing of IONSYS and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; IONSYS REMS; ADDICTION, ABUSE, AND MISUSE; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. Serious, life‑threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation. Only the patient should activate dosing. ( 2.1, 5.1) IONSYS is for use only in patients in the hospital. Discontinue IONSYS before patients leave the hospital. ( 5.1) Because of the risk of respiratory depression from accidental exposure, IONSYS is available through a restricted program called the IONSYS REMS Program. Healthcare facilities that dispense IONSYS must be certified in this program and comply with the REMS requirements ( 5.2) IONSYS exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing, and monitor regularly for these behaviors and conditions. ( 5.3) Concomitant use with CYP 3A4 inhibitors (or discontinuation of CYP 3A4 inducers) can result in a fatal overdose of fentanyl. ( 5.4, 7, 12.3) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.5, 7)