"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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Mechanism Of Action
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. When patients titrated themselves to analgesic effect with IONSYS, 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 [see WARNINGS AND PRECAUTIONS and OVERDOSAGE].
Effects on the Cardiovascular System Fentanyl may produce 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.
Effects on Central Nervous System
Central nervous system effects, such as sedation and depression of respiration, increase with increasing serum fentanyl concentrations. 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.
Effects on Gastrointestinal Tract and Other Smooth Muscle
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.
While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination.
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 for 10 minutes, 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. At treatment initiation, the amount of fentanyl absorbed is expected to be approximately 16 mcg (see Figure 9A and Figure 9B). 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 fentanyl serum concentration was 1.94 ± 0.43 ng/mL. Pharmacokinetic data from illustrative dosing regimens are represented in Table 4. 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%).
The delivery of fentanyl from IONSYS is similar whether applied on the upper outer arm or the chest. When IONSYS is placed on the lower inner arm, the delivery of fentanyl is approximately 20% lower. Other application sites have not been evaluated.
Figure 9 : Serum Fentanyl Concentration Following 40
mcg IONSYS® (fentanyl) Compared to IV Fentanyl
A. First Hour of a Representative Treatment*
B: Last Hour and upon Termination of a Representative
* IONSYS® 40 mcg: 2 sequential doses over 20 minutes every hour for 23 hours and 20 minutes; IV: 80 mcg dose over 20 minutes every hour for 23 hours and 20 minutes.
Table 4: Mean
Pharmacokinetic Parameters Based on Representative and Maximum Dosing Regimens
|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|
|Cmax (ng/mL)||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)
aRepresentative dosing regimen based on number of doses administered by patients in Phase 3 clinical studies
bMaximum 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, α1-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.
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 9B). 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.
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.
Age did not affect fentanyl absorption from IONSYS.
Sex differences have been reported for hepatically metabolized drugs. Generally, those that are metabolized by CYP3A4 appear to be eliminated faster by women in many cases. There have been no reports on gender differences in fentanyl pharmacokinetics.
Race did not affect fentanyl absorption from IONSYS.
No studies specific to IONSYS in patients with renal impairment have been conducted. In the literature, the pharmacokinetics of fentanyl in patients with severe renal disease was compared to healthy patients. Plasma fentanyl concentrations decreased faster following an IV fentanyl administration in those with renal disease than in the control group, indicating more rapid clearance in the former. As renal clearance of fentanyl is only 10%, a decrease in renal function would not be expected to have a significant effect on the clearance of fentanyl.
No studies specific to IONSYS in patients with hepatic impairment have been conducted. In the literature, fentanyl appears to be affected more by hepatic blood flow than by hepatocellular function. The plasma concentration time profiles for the control and cirrhotic patients were similar and not significantly different with respective average elimination half-life values of 10.8 mL/min/kg vs. 11.3 mL/min/kg and volume of distribution values of 3.81 L/kg vs. 4.41 L/kg. In addition, the pharmacokinetics of fentanyl in patients with end-stage liver disease who were undergoing hemodialysis to those in normal patients was studied. While differences between groups were not statistically significant, fentanyl clearance values were reported to be lower for the hepatically impaired patients.
Drug Interaction Studies
Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4). The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52%–420%) increase in fentanyl AUC0-∞. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, or grapefruit juice) 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 respiratory depression for an extended period of time and discontinue IONSYS if warranted [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Co-administration with agents that induce CYP3A4 activity may decrease plasma concentration of fentanyl following use of IONSYS. Discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration.
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 IONSYS or matching placebo IONSYS was applied. Patients were instructed to use IONSYS for pain. 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 5 below.
Table 1: Percentage of Patients Requiring Supplemental
IV Fentanyl Medication in Hours 0-3 (Mean Quantity Administered) in Studies 1,
2, and 3
|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. Efficacy demonstrated in all three studies as demonstrated by the last mean pain intensity scores recorded during the 24-hour treatment period are presented in Table 6.
Table 2: Mean Pain Intensity
Score in Studies 1, 2, and 3
|Study 1 (NRSa)||3.4||5.3||<0.0001|
|Study 2 (VASb)||31||41||0.0474|
|Study 3 (VASb)||21||37||0.0006|
|aVerbal numerical rating scale 0-10 at 24 hours or at
bVisual analogue scale, 0-100 mm at 24 hours or at discontinuation
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 7).
Table 3: Percentage of
Patients Who Withdrew due to Inadequate Analgesia in Studies 1, 2, and 3
|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 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 per patient (range of 0 to 93 doses). The majority of patients (56.5%) used between 11 to 50 doses. One percent of patients required a second IONSYS within 24 hours, after exhausting the first IONSYS.
Last reviewed on RxList: 9/8/2015
This monograph has been modified to include the generic and brand name in many instances.
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