Fentanyl iontophoretic transdermal system

Chemical Characteristics Of Drug Substance And Product

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. 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 (see Figure 8) 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 for IONSYS removal from the skin and during disposal [see DOSAGE AND ADMINISTRATION]. A siliconized clear, plastic release liner covers the hydrogels and must be removed and discarded prior to placement on the skin. IONSYS is powered by a 3-volt lithium battery.

Figure 8 : IONSYS® (fentanyl iontophoretic transdermal system)

*Light is off or on (blinks and displays red or green color light)

The following serious adverse reactions are described elsewhere in the labeling:

• Life-Threatening respiratory Depression [see WARNINGS AND PRECAUTIONS]
• Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
• Interactions with Benzodiazepines or Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
• Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
• Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
• Severe Hypotension [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Withdrawal [see WARNINGS AND PRECAUTIONS]
• Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]

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)

NOTE: Patients reported as having “Nausea and vomiting” are included in “Nausea” and “Vomiting” in Table 1.

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.

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].

Clinical Presentation

Acute overdose with IONSYS can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see CLINICAL PHARMACOLOGY].

Treatment Of Overdose

In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to fentanyl overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to fentanyl overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of fentanyl in IONSYS, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist may precipitate acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

>10%

Nausea (39%)

Application site reaction, erythema (14%)

Vomiting (12%)

1-10%

Headache (9%)

Pruritus (6%)

Urinary retention (3%)

Anemia (3%)

Dizziness (3%)

Hypotension (2%)

Frequency Not Defined

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, myalgia

Nervous system: Insomnia, anxiety, somnolence, confusion, paresthesia, hypoesthesia, 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, vesiculobullous rash, oozing/bleeding, inflammation/erythema, and general rash and general sweating

Special senses: Abnormal vision; blurred vision

Urogenital system: Impaired urination, hematuria, urinary tract infection, urinary urgency, dysuria

Postmarketing Reports

Application site reactions: Urticaria, application site discharge, erosion, hyperesthesia, pustules, rash and scab, application site bleeding, application site infection, necrosis

Mechanism of Action

Mu-opioid receptor agonist with the principle effect resulting in analgesia

In addition to analgesia, undesirable pharmacodynamic effects from opioid agonists include CNS depression (eg, sedation, respiratory depression/hypoventilation); orthostatic hypotension; alterations in mood, euphoria and dysphoria, and drowsiness; increased tone and decreased propulsive contractions of smooth muscle of the GI tract; and urinary retention or urgency

Absorption

Compared to IV fentanyl, 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

Absorption is similar whether applied on the upper outer arm or the chest; when placed on the lower inner arm, the delivery of fentanyl is approximately 20% lower

AUC per dose: 0.51-0.57 ng/mL

Peak plasma concentration: 1.3-1.94 ng/mL

Distribution

Distribution half-life (IV, 3-compartment model): 6 min, 1 hr, 16 hr (terminal half-life)

Protein bound: 79-87%; binds to erythrocytes, alpha-1-acid glycoproteins, and plasma albumin; ionization of drug and blood pH affect binding

Vd (IV, steady-state): 833 L

Metabolism

Metabolized by CYP3A4 to norfentanyl and other inactive metabolites

Elimination

Clearance (IV): 53 L/hr

Excretion (IV within 72 hr): 75% urine (>10% representing unchanged drug); 9% feces (primarily as metabolites)

A decline in fentanyl concentration after termination of treatment and the terminal half-life is similar to that following IV administration; This suggests a negligible continued absorption of fentanyl remaining on the skin

Instructions

After titrating to acceptable level of analgesia using another opioid analgesic, apply one Ionsys system transdermally to healthy, unbroken/intact, nonirritated, and nonirradiated skin on the chest or upper outer arm only

Each activation provides a 40-mcg dose of fentanyl

It is important to instruct patients how to operate Ionsys to self-administer doses of fentanyl as needed to manage their postoperative pain

Allow only the patient to self-administer doses

Each on-demand dose is delivered over a 10-minute period

Each system operates up to 24 hr or 80 doses, whichever comes first

Preparation of application site

Choose healthy, unbroken skin on the upper outer arm of chest only

Clip excessive hair if necessary; do not shave as this may irritate skin

Clean site with alcohol and let it dry

Do not use soaps, lotions, or other agents

Wear gloves when handling Ionsys

Assembly and application of Ionsys

See prescribing information for diagrams for assembly

Apply by peeling of clear plastic liner covering the adhesive and hydrogels

Take care not to pull on the red tab while removing the clear plastic liner when preparing to apply the system to the patient; the red tab is only to be used when separating Ionsys for disposal

Press and hold Ionsys firmly in place, with the sticky side down, onto patient’s skin for at least 15 seconds; press with your fingers around the edges to be sure it adheres to the skin, but do not press the dosing button

Occasionally, the system may loosen from the skin; if this occurs, secure it to patient’s skin by pressing the edges with fingers or securing with a nonallergenic tape to be sure that all edges make complete contact with the skin

After taping, if Ionsys beeps again, remove and dispose; place a new system on a different skin site

Operation of Ionsys

A recessed button is located on the top; to initiate administration of a fentanyl dose, the patient must press and release the button twice within 3 seconds

System 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 rotating circle 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

The system 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 the system is working properly

Each Ionsys will cease functioning at the end of 24 hr 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

Removal

May be removed at any time

Once Ionsys has been removed, the same system must not be reapplied

At the end of 24 hr 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 the system from the patient

Disposal

Contact with the hydrogels contained can result in a fatal overdose of fentanyl

Using gloves, handle the used Ionsys by the sides and top while avoiding contact with the hydrogel

Dispose in accordance with state and federal regulations for controlled substances

The used red bottom housing of Ionsys contains a significant amount of fentanyl that could cause a fatal overdose of fentanyl

To dispose of a used Ionsys

• 1. With gloves on, pull the red tab to separate the red bottom housing containing fentanyl from Ionsys
• 2. Fold the red housing in half with the sticky side facing in
• 3. 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
• 4. 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

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

Assemble and use immediately after removal from the individually sealed package

Do not use this medication unless you are already being treated with a similar opioid (narcotic) pain medicine and your body is tolerant to it. Opioid medicines include morphine (Kadian, MS Contin, Oramorph, and others), oxycodone (OxyContin), and hydromorphone (Dilaudid). Talk with your doctor if you are not sure you are opioid-tolerant.

Before you receive this medication, tell your doctor if you are allergic to fentanyl or any other medications, or if you have:

• a breathing disorder such as chronic obstructive pulmonary disease (COPD);
• a history of head injury or brain tumor;
• a heart rhythm disorder;
• liver disease; or
• kidney disease.

If you have any of these conditions, you may need a dose adjustment or special tests to safely use this medication.

FDA pregnancy category C. This medication may be harmful to an unborn baby, and could cause addiction or withdrawal symptoms in a newborn. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Fentanyl may also cause addiction and withdrawal symptoms in a nursing infant. Do not use fentanyl transdermal without telling your doctor if you are breast-feeding a baby.

Older adults may be more likely to have side effects from this medicine.

Fentanyl transdermal may be habit-forming and should be used only by the person it was prescribed for. This medication should never be shared with another person, especially someone who has a history of drug abuse or addiction.

• Pain Management
• Pain Management: Musculoskeletal Pain