"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"...
(Generic versions may still be available.)
In clinical settings, fentanyl exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Fentanyl may increase the patient's tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized.
In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers and the cough reflex, and constricts the pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting by directly stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of opioids. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain.
At therapeutic dosages, fentanyl usually does not exert major effects on the cardiovascular system. However, some patients may exhibit orthostatic hypotension and fainting. Histamine assays and skin wheal testing in humans indicate that clinically significant histamine release rarely occurs with fentanyl administration. Assays in humans show no clinically significant histamine release in dosages up to 50 mcg /kg.
When patients titrated themselves to analgesic effect with IONSYS™ 40 mcg, serum concentrations were in the range of 0.4 to 1.5 ng/mL over the 24-hour dosing period.
Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations and may occur at any time during therapy, especially for patients who have an underlying pulmonary condition or who receive doses of opioids or other CNS drugs associated with hypoventilation in addition to IONSYS™. The respiratory effects of IONSYS™ should be monitored by clinical evaluation, including oxygen saturation, respiratory rate, and degree of sedation. After delivery of the maximum number of doses in the shortest possible time period (80 consecutive doses delivered over approximately 13 hours), the fentanyl serum concentration was in the range of 1.51 to 2.37 ng/mL, which is in the range that could result in respiratory depression.
Fentanyl may produce bradycardia.
Central nervous system effects, such as sedation and depression of respiration, increase with increasing serum fentanyl concentrations.
Unless otherwise specified, the clinical pharmacology studies described in this section were performed in healthy adult volunteers. Volunteers were administered naltrexone to antagonize the opioid effects of fentanyl.
At the initiation of each dose, an electrical current is activated, which moves a dose of fentanyl from the drug-containing reservoir through the skin and into the systemic circulation. Compared to IV fentanyl administration, fentanyl concentrations in blood increase slowly with IONSYS™ activation and continue to increase for approximately 5 minutes after the completion of each 10-minute dose.
The systemic absorption of fentanyl from IONSYS™ increases as a function of time, and this increase appears to be independent of frequency of dosing. When a dose of 40 mcg is administered at treatment initiation, the amount of fentanyl absorbed is expected to be approximately 16 mcg (see Figures 1A, IB). In clinical pharmacokinetic studies, on-demand dosing was initiated immediately after IONSYS™ application. This resulted in absorption of a 40 mcg fentanyl dose by about 10 hours post treatment initiation. Thereafter, a 40-mcg dose of fentanyl is delivered with each activation.
After delivery of the maximum number of doses in the shortest possible time period (80 consecutive doses delivered over approximately 13 hours), the average maximum fentanyl serum concentration was 1.94 + 0.43 ng/mL. Pharmacokinetic data from illustrative dosing regimens are represented in Table 1. When IONSYS™ was applied without activating the current, the average absorption rate for fentanyl over 24 hours was 2.3 mcg/h.
Inter-subject variability in fentanyl AUC following IONSYS™ treatment (33%) was comparable to IV fentanyl treatment (28%), suggesting that the iontophoretic transdermal system does not add to the inherent between-subject variability in fentanyl AUC.
The delivery of fentanyl from IONSYS™ is similar whether applied on the upper outer arm or the chest. When the system is placed on the lower inner arm, the delivery of fentanyl is approximately 20% lower. Other application sites have not been evaluated.
A: First Hour of a Representative Treatment*
B. Last Hour and Upon Termination of a Representative Treatment*
*IONSYS™ 40 mcg: 2 sequential doses over 20 minutes every hour tor 23 hours and 20 minutes; IV: 80 mcg dose over 20 minutes every hour for 23 hours, and 20 minutes.
Table 1: Mean Pharmacokinetic Parameters Based on Representative
and Maximum Dosing Regimens (n=23)
|Parameter||48a doses (two sequential doses every hour for 23 hours and 20 minutes)||80b sequential doses (one dose every ten minutes for 13 hours and 20 minutes)|
|AUC per on-demand dose (ng/mL)||0.57 ± 0.13*||0.51 ± 0.16**|
|1.3 ± 0.3||1.94 ± 0.43|
| *AUC for this dosing regimen is value estimated between 23-24 hours
**Average AUC over all doses delivered during the treatment duration (13.33 hours)
a Representative dosing regimen
b Maximum theoretical dosing
Fentanyl administered intravenously exhibits a three-compartment disposition model. In healthy volunteers after IV administration, the estimated initial distribution half-life was about 6 minutes; the second distribution half-life was about 1-hour; and the terminal half-life was about 16 hours. The average volume of distribution for fentanyl at steady state following IV administration is 833 L.
Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%. Fentanyl binds to erythrocytes, oq-acid glycoproteins, and plasma albumin.
Binding is independent of drug concentration over the therapeutic range. Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in blood pH may alter ionization of fentanyl and therefore its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood.
In humans, fentanyl is metabolized primarily by cytochrome P450 3A4-mediated N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. The average clearance in healthy subjects following IV administration was observed to be 53 L/h. Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites, with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.
A decline in fentanyl concentration after termination of treatment and the terminal half-life is similar following IV administration of fentanyl and IONSYS™ (see Figure IB). This suggests a negligible contribution from continued absorption of fentanyl remaining in the skin.
Skin does not metabolize fentanyl administered transdermally. This was determined in a human keratinocyte cell assay.
Agents Affecting Cytochrome P450 3A4
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.
Literature suggests that clearance of fentanyl may be reduced and the terminal half-life prolonged in the elderly (see PRECAUTIONS). In a pharmacokinetic study conducted in 63 healthy volunteers where several demographic factors (age, race, gender, and body mass index) were evaluated, none of these factors had a significant effect on the extent of drug absorption (AUC) following administration of IONSYS™.
The efficacy and safety of IONSYS™ for treatment of short-term acute pain were evaluated in three placebo-controlled studies in postoperative patients. The patients were predominantly female (70-83%) and Caucasian (79-84%), and their mean age was 45-54 years (range, 18-90 years). Patients were enrolled while in the recovery room shortly after major surgery (predominantly lower abdominal or orthopedic) if they were expected to require at least 24 hours of parenteral opioid treatment and were not opioid tolerant; their ASA (American Society of Anesthesiologists) physical status was I, II, or III; and their postsurgical recovery was expected to be uncomplicated. Across the trials, 154 patients were ASA I status (21%); 435 patients were ASA II status (60%); and 138 patients were ASA III status (19%). Administration of long-lasting or continuous regional analgesics, or any non-opioid analgesics was not permitted in the studies. Patients who remained in the studies for three or more hours using IONSYS™ (or the control) for patient-controlled analgesia (PCA) were considered evaluable.
In the immediate postoperative period, patients were titrated to comfort with IV fentanyl or morphine per hospital protocol. Once comfortable, patients were randomized and the IONSYS™ or matching placebo system was applied. Patients were instructed to use the system for pain relief. Supplemental IV fentanyl was administered by bolus injection as needed to achieve comfort up to three hours post-enrollment. The percentage of patients who used rescue medication during these three hours, as well as the mean amount of rescue medication used, is shown in Table 2 below.
Table 2: Percentage of Patients Requiring Supplemental IV
Fentanyl Medication in Hours 0-3 (Mean Quantity Administered)
|Study 1||45 % (83 mcg)||52 % (102 mcg)|
|Study 2||48 % (100 mcg)||55 % (95 mcg)|
|Study 3||34 % (78 mcg)||36 % (76 mcg)|
After Study Hour 3, IONSYS™ alone or the placebo treatment alone was used to provide analgesia.
In each of the three randomized, double-blind, placebo-controlled trials, fewer patients discontinued for lack of efficacy from three hours to twenty-four hours after IONSYS™ application (see Table 3).
Table 3: Percent (n) of Patients Who Withdrew Due to Inadequate
Analgesia Hours 3-24
|Study 1||27 % (64/235)||57% (116/204)||< 0.0001|
|Study 2||25 % (36/142)||40 % (19/47)||0.049|
|Study 3||8 % (6/77)||41 % (9/22)||0.0001|
The last mean pain intensity scores recorded during the 24-hour treatment period are presented in Table 4.
Table 4: Mean Pain Intensity Score
|Study 1 (NRSa)||3.4||5.3||< 0.0001|
|Study 2 (VASb)||31||41||0.0474|
|Study 3 (VASb)||21||37||0.0006|
| a Verbal numerical rating score 0-10 at 24 hours or at discontinuation
b Visual analogue scale, 0-100 mm at 24 hours or at discontinuation
The type of surgical procedure did not influence the trends in efficacy endpoints.
The efficacy of IONSYS™ was similar across the range of body mass indices studied ( < 25 to ≥ 40 kg/m2 Body Mass Index). Patients who completed 24 hours of IONSYS™ treatment in the controlled studies used a wide range of the available 80 doses, with a mean of 29 doses/patient (range of 0-93 doses). The majority of patients (56.5%) used between 11 to 50 doses. One percent of patients required a second system within 24 hours, after exhausting the first system.
Last reviewed on RxList: 6/12/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Ionsys Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Chronic Pain/Back Pain
Find tips and advances in treatment.