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Ionsys (Fentanyl Hydrochloride Transdermal) - Description and Clinical Pharmacology

 
 



IONSYS™ (fentanyl iontophoretic transdermal system)
40 mcg*/activation

CII

Patient-activated
* Equals to 44.4 mcg fentanyl HCl

DESCRIPTION

IONSYS™ (fentanyl iontophoretic transdermal system) is a patient-controlled iontophoretic transdermal system providing on-demand systemic delivery of fentanyl, an opioid agonist, for up to 24 hours or a maximum of 80 doses, whichever comes first.

The chemical name is propanamide, N-phenyl-N-[1-(2-phenylethyl)-4- piperidinyl] monohydrochloride. The structural formula is:

The molecular weight of fentanyl hydrochloride is 372.93, and the empirical formula is C22H28N2O·HCl. The n-octanol:water partition coefficient is 860:1; the pKa is 8.4.

The active ingredient in IONSYS™ is fentanyl HCl, which is equivalent to 40 mcg per dose of fentanyl free base. IONSYS™ contains 10.8 mg of fentanyl hydrochloride equivalent to 9.7 mg of fentanyl. IONSYS™ is designed to deliver a 40-mcg dose of fentanyl (equivalent to 44.4 mcg of fentanyl hydrochloride) over a 10-minute period upon each activation of the dose button (see DOSAGE AND ADMINISTRATION).

The inactive ingredients in the IONSYS™ hydrogels consist of cetylpyridinium chloride, USP; citric acid, USP; polacrilin; polyvinyl alcohol; sodium citrate, USP; sodium chloride, USP; sodium hydroxide; and purified water, USP.

System Components and Structure

Each IONSYS™ system is composed of a plastic top housing that contains the battery and electronics, and a red plastic bottom housing containing two hydrogel reservoirs and a polyisobutylene skin adhesive. Only one of the hydrogels (the anode, located under the dosing button) contains fentanyl HCl, along with inactive ingredients. The other hydrogel (the cathode) contains only pharmacologically inactive ingredients. The bottom housing has a red tab that is used only for system removal from the skin and during disposal (see DOSAGE AND ADMINISTRATION, Disposal). A siliconized clear, plastic release liner covers the hydrogels and must be removed and discarded prior to placement on the skin. The system is powered by a 3-volt lithium battery.

IONSYS™ (fentanyl iontophoretic transdermal system)

IONSYS™ (fentanyl iontophoretic transdermal system)

CLINICAL PHARMACOLOGY

Pharmacology

Fentanyl is an opioid analgesic. Fentanyl interacts predominantly with the opioid μ-receptor. These μ-binding sites are discretely distributed in the human brain, spinal cord, and other tissues.

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.

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.

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.

Pharmacodynamics

Analgesia

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.

Respiratory Effects

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, PRECAUTIONS and OVERDOSAGE for additional information on respiratory depression.

Cardiovascular Effects

Fentanyl may produce bradycardia.

CNS Effects

Central nervous system effects, such as sedation and depression of respiration, increase with increasing serum fentanyl concentrations.

Pharmacokinetics

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.

Absorption

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, 1B). 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.

 

 

Table 1 Mean Pharmacokinetic Parameters Based on Representative and Maximum Dosing Regimens (n=23)
Dosing Regimen

*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

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**
Cmax
(ng/mL)
1.3±0.31.94±0.43

Distribution

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.

Metabolism

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 1B). 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.

Drug Interactions

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.

Special Populations

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™.

CLINICAL STUDIES

Placebo-controlled Trials

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)
IONSYS™Placebo
Study 145 % (83 mcg)52 % (102 mcg)
Study 248 % (100 mcg)55 % (95 mcg)
Study 334 % (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
StudyIONSYS™
n=454
Placebo
n=273
p-value
Study 127 % (64/235)57 % (116/204)<0.0001
Study 225 % (36/142)40 % (19/47)0.049
Study 38 % (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
StudyIONSYS™
n=454
Placebo
n=273
p-value

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

Study 1 (NRSa)3.45.3<0.0001
Study 2 (VASb)31410.0474
Study 3 (VASb)21370.0006

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.

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