Ionsys

1 

ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
IONSYS 40 micrograms per dose transdermal system 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each IONSYS system contains fentanyl hydrochloride equivalent to 9.7 mg of fentanyl and delivers 
40 micrograms fentanyl per dose, to a maximum of 80 doses (3.2 mg/24 hours). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Transdermal system 
 
IONSYS is composed of an electronic controller and a drug unit with two hydrogels. The controller is 
white with the identifier ‘IONSYS®’ and has a digital display, a light window, and a recessed dose 
activation button. The drug unit is blue on the side that connects to the controller and has a red bottom 
housing containing the hydrogels, one of which contains the fentanyl. The assembled IONSYS 
product measures 47 mm x 75 mm.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
IONSYS is indicated for the management of acute moderate to severe post-operative pain in adult 
patients. 
 
4.2 Posology and method of administration 
 
IONSYS is restricted to hospital use only. Treatment should be initiated by and remain under the 
guidance of a physician experienced in the management of opioid therapy. Due to the well-known 
potential of abuse of fentanyl, physicians should evaluate patients for a history of drug abuse (see 
section 4.4). 
 
Posology 
 
Patients should be titrated to an acceptable level of analgesia prior to initiating use of IONSYS (see 
section 5.1). 
 
IONSYS should only be activated by the patient. 
 
Each dose of IONSYS delivers 40 micrograms of fentanyl over a 10 minute period, to a maximum of 
240 micrograms per hour (6 doses each of 10 minutes duration). IONSYS will operate for 24 hours 
after the system is assembled or for 80 doses, whichever comes first, and then becomes inoperative.  
 
After 24 hours or 80 doses, a new system should be applied if necessary. Each new system should be 
placed on a new skin site. With each new IONSYS application the patient may use IONSYS more 
frequently than during the remainder of the 24 hour dosing period, due to a lower absorption of 
fentanyl from the system for the first few hours (see section 5.2). 
 
The maximum treatment duration is 72 hours, although the majority of patients should only need one 
system. 
 

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Patients should not wear more than one system at a time.  
 
Used systems should not be reapplied to a patient. 
 
IONSYS should be removed before the patient is discharged. 
 
Elderly patients  
As with all fentanyl products, the clearance of fentanyl may be reduced in elderly patients, with a 
consequent increase in half life. No specific dose adjustment is required in elderly patients. However 
elderly patients should be observed closely for adverse effects of fentanyl (see sections 4.4 and 4.8). 
 
Hepatic or renal impairment 
IONSYS should be administered with caution to patients with moderate or severe hepatic or renal 
impairment (see section 4.4). 
 
Paediatric population 
The safety and efficacy of IONSYS in children and adolescents younger than 18 years of age has not 
been established. Currently available data are described in section 4.8, but no recommendation on 
posology can be made. 
 
Method of administration  
 
IONSYS is for transdermal use only. 
 
Precaution to be taken before manipulating or administering the product 
Gloves should be worn when manipulating IONSYS. To avoid oral ingestion of the fentanyl-
containing hydrogel, which may cause life-threatening hypoventilation or death, the hydrogel must not 
touch the mouth or other mucosal areas. 
 
Patients should not get IONSYS wet.  Prolonged contact with water could affect system performance 
and cause the system to fall off.  
 
Preparation of application site 
IONSYS should be applied to intact, non-irritated and non-irradiated skin. IONSYS should not be 
placed on abnormal skin sites, such as scars, burns, tattoos, etc. IONSYS should also not be placed on 
skin on which topical medicines have been applied. Hair at the application site should be clipped (not 
shaved) before system application. IONSYS should not be applied to a previously used skin site. 
The application site should be wiped with a standard alcohol swab and the skin should be allowed to 
dry completely before IONSYS is applied. No soaps, oils, lotions, or any other agents that might 
irritate the skin or alter its absorption characteristics should be used to clean the application site. 
 
Assembly of IONSYS 
IONSYS should not be used if the seal on the tray or the sachet containing the Drug Unit is broken or 
damaged. 

 

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Gloves should be worn during the assembly of IONSYS. The tray is opened by pulling back on the 
tray lid. The sachet containing the Drug Unit should be opened starting at the pre-cut notch, then by 
carefully tearing along the top of the sachet. The Drug Unit should be removed from the sachet and the 
Controller should be snapped on by aligning the shape and firmly pressing the two parts together.  
 
When assembled, the digital display of the Controller will complete a short self-test during which 
there will be an audible beep, the red light will flash 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 flash at a slow 
rate to indicate IONSYS is ready for application. 
 
Application of IONSYS 
The clear plastic film covering the adhesive should be removed and discarded with care taken not to 
touch the hydrogels. IONSYS should be pressed firmly in place for at least 15 seconds with the sticky 
side down on the skin of the chest or upper arm of the patient. Pressure should be applied with the 
fingers around the outer edges to ensure adhesion to the skin site. If at any point during use the system 
loosens from the skin, a non-allergenic tape may be used to secure the edges to ensure complete 
contact with the skin. When applying tape, care should be taken not to tape over the light window, the 
digital display, or the dosing button. The dosing button must not be pressed. 
 
For further details, see section 6.6. 
 
Dose delivery  
A recessed dosing button is located on the Controller of IONSYS. To initiate administration of a 
fentanyl dose, the patient should press and release the dosing button twice within 3 seconds. IONSYS 
should only be activated by the patient. 
 
Upon successful dose initiation, IONSYS will emit a beep indicating the start of delivery. The green 
light will change from a slow flash rate to a rapid flash rate and the digital display will alternate 
between a rotating circle and the number of completed doses during the entire 10-minute dose delivery 
period. The next dose cannot be initiated until the previous 10-minute delivery period is complete. 
Pressing the button during delivery of a dose will not result in additional fentanyl being administered. 
After the 10-minute dose has been completely delivered, the green light will return to a slow flash rate, 
the digital display will show the number of doses that have been delivered, and IONSYS will be ready 
to be used again by the patient. 
 
At the end of 24 hours of use, or after 80 doses have been administered, the green light will switch off 
and the number of doses delivered will flash on and off. The flashing digital display may be turned off 
by pressing the dose button for six seconds. 
 
Removal  
IONSYS is removed from the patient by lifting the system at the red tab and peeling it away from the 
skin site. Gloves must be worn while removing IONSYS from the skin and care should be taken to 
avoid touching the hydrogels. If the medicinal product contacts the skin during removal, the contact 
area should be thoroughly rinsed with water without using any soap. 
 
IONSYS may be removed at any time. However, once a system has been removed, the same system 
should not be reapplied. If the patient requires additional treatment for pain, a new system may be 
applied to a new skin site on the upper outer arm or chest. 
 
Special precautions for disposal should be followed (see section 6.6). 
 

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Troubleshooting 
Each IONSYS system is designed to deliver up to 80 10-minute doses of fentanyl over a period of 
24 hours. The table below represents the different error messages that may occur, together with the 
probable cause and the action to be taken. 
 
Error message/feedback Probable 

cause 
Action required 

• No light 
• No beeps 
• No display 

Low battery 
or defective 
system 

1. Do not use the system 
2. Dispose of system per 

instructions in Section 6.6 
3. Place a new system on a 

different skin site 
• Blinking red light for 15 seconds 
• Beeping for 15 seconds 
• System is not securely adhered  

Poor skin 
contact 

1. Secure system to patient’s skin 
by pressing the edges firmly or 
by applying non-allergenic tape 

2.  If system beeps again, then 
remove and dispose of system, 
and place a new system on a 
different skin site.  

• Continuous blinking red light  
• Continuous beeping  
• Steady display number 

System 
error 

1. Remove system from patient 
2. Hold down dosing button until 

beeping stops and display goes 
blank 

3. Dispose of system per 
instructions in Section 6.6 

4. Place a new system on a 
different skin site 

• No light 
• No beeps 
• Blinking display number  

End of use 
at 24 hours 
or 80 doses 

1. Remove system from patient 
2. Hold down dosing button until 

display goes blank 
3. Dispose of system per 

instructions in Section 6.6 
4. Place a new system on a 

different skin site 
 
If device failure or malfunction is suspected by a healthcare professional, IONSYS should be 
immediately removed from the patient and The Medicines Company contacted straightaway.  
 
The healthcare professional must ensure the patient understands that if they suspect a device failure or 
malfunction, they must immediately inform a healthcare professional. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Severe respiratory depression or cystic fibrosis. 
 
4.4 Special warnings and precautions for use 
 
Before any surgery, the healthcare professional should ensure that the patient has been properly 
informed on how to use IONSYS post-operatively. 
 
A potentially dangerous amount of fentanyl remains in the IONSYS system after use. For disposal 
instructions, see section 6.6. 
 

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IONSYS should be removed before a magnetic resonance imaging (MRI) procedure, cardioversion, 
defibrillation, X-ray, CT scan or diathermy is undertaken. 
 
Excessive sweating may reduce delivery of fentanyl.  
 
Respiratory depression  
 
IONSYS should only be activated by the patient, to avoid potential overdosing. 
 
Significant respiratory depression may occur with IONSYS; patients must be observed for these 
effects (see section 4.9).  
 
The use of concomitant CNS-active medicinal products may increase the risk of respiratory depression 
(see section 4.5). 
 
Chronic pulmonary disease  
 
In patients with chronic obstructive pulmonary disease or patients with conditions pre-disposing them 
to hypoventilation, more severe adverse reactions may be experienced. In such patients, opioids may 
decrease respiratory drive and increase airway resistance. 
 
Head injuries and increased intracranial pressure  
 
Fentanyl should not be used in patients who may be particularly susceptible to the intracranial effects 
of CO2 retention, such as those with evidence of increased intracranial pressure, impaired 
consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. Fentanyl 
should be used with caution in patients with brain tumours or other significant space occupying lesions 
of the brain. 
 
Cardiac disease  
 
Fentanyl may produce bradycardia or hypotension and should, therefore, be administered with caution 
to patients with bradyarrhythmias or any significant cardiovascular disease. 
 
Paralytic ileus  
 
IONSYS should be used with caution in patients with paralytic ileus. 
 
Abuse potential and dependence  
 
Fentanyl has a well-known abuse potential. Patients with a prior history of drug dependence/alcohol 
abuse are more at risk to develop dependence and abuse in opioid treatment. Physicians should 
evaluate patients for a history of drug abuse and follow such patients closely.  
 
Tolerance, physical dependence, and psychological dependence may develop upon repeated 
administration of opioids. Iatrogenic addiction following opioid administration is rare. Fentanyl can be 
abused in a manner similar to other opioid agonists. Abuse or intentional misuse of IONSYS may 
result in overdose and/or death. 
 
Hepatic disease  
 
Fentanyl is metabolised into inactive metabolites in the liver. Hepatic disease may delay elimination. 
Patients with hepatic impairment should be observed carefully for signs of fentanyl toxicity. 
 
Renal disease  
 

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Less than 10% of administered fentanyl is excreted unchanged by the kidney. Unlike morphine, no 
active fentanyl metabolites are eliminated by the kidney. Data obtained with intravenous fentanyl in 
patients with renal failure suggest that the volume of distribution of fentanyl may be changed by 
dialysis. This may affect serum concentrations. If patients with renal impairment receive IONSYS, 
they should be observed carefully for signs of fentanyl toxicity. 
 
Elderly patients  
 
Elderly patients should be observed carefully for adverse effects of fentanyl during IONSYS 
administration (see sections 4.2 and 4.8). 
 
Obese patients  
 
The overall adverse reaction profile for morbidly obese patients (BMI > 40) does not suggest a 
meaningful difference in safety compared to patients with BMI ≤ 40. However, caution is advised 
when prescribing IONSYS in morbidly obese patients because they may be at increased risk of other 
comorbid respiratory conditions (i.e., sleep apnoea) potentially pre-disposing them to hypoventilation 
or more severe adverse reactions (see section 4.8). 
 
Hearing impairment  
 
IONSYS should be used with caution in patients with hearing impairment who might not be able to 
hear the audible signals from the system.  
 
Thoracic/chest and upper abdominal surgeries  
 
Only limited data are available in patients with thoracic/chest and upper abdominal surgeries. IONSYS 
should, therefore, be used with caution in these patients.  
 
Physical status  
 
The safety of IONSYS has not been established in patients with American Society of 
Anesthesiologists (ASA) physical status classification IV (i.e. patients with a severe systemic disease 
that is a constant threat to life). 
 
Patients with genetic polymorphisms affecting CYP3A4 and CYP3A5 
 
Published literature indicates potential for increased fentanyl exposure in patients with genetic 
polymorphisms affecting CYP3A4 and CYP3A5, with a small variability in concentrations with 
transdermal administration; therefore, IONSYS should be used with caution in these patients (see 
section 5.2) 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
The concomitant use of other central nervous system depressants including other opioids, sedatives or 
hypnotics, general anaesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating 
antihistamines, and alcoholic beverages, may produce additive depressant effects. Hypoventilation, 
hypotension, and profound sedation or coma may occur. Therefore, the use of any of these medicinal 
products concomitantly with IONSYS requires special patient care and observation. 
 
Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by 
CYP3A4. Itraconazole, a potent CYP3A4 inhibitor, at 200 mg/day orally for 4 days had no significant 
effect on the pharmacokinetics of intravenous fentanyl. Oral ritonavir, one of the most potent CYP3A4 
inhibitors, reduced the clearance of intravenous fentanyl by two thirds. The concomitant use of potent 
CYP3A4 inhibitors (e.g., as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, and 
nelfinavir) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, 
fluconazole, fosamprenavir, grapefruit juice, and verapamil) with IONSYS may result in an increase in 

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fentanyl plasma concentrations, which could increase or prolong both the therapeutic effect and 
adverse reactions, and may cause serious respiratory depression. In this situation, special patient care 
and observation are appropriate. The concomitant use of ritonavir or other potent or moderate 
CYP3A4 inhibitors and IONSYS is not recommended unless the patient is closely monitored. 
 
The concomitant use of partial opioid agonists/antagonists (e.g. buprenorphine, nalbuphine, 
pentazocine) is not recommended. They have high affinity to opioid receptors with relatively low 
intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce 
withdrawal symptoms in opioid dependant patients. 
 
Serotoninergic medicinal products 
 
Co-administration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-uptake 
Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase 
Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening 
condition.  
 
IONSYS is not recommended for use in patients who have received monoamine oxidase (MAO) 
inhibitors within 14 days because severe and unpredictable potentiation by MAO inhibitors has been 
reported with opioid analgesics 
 
Interaction studies have only been performed in adults.  
 
Topical medicines 
 
Application of the IONSYS system on skin on which any topical medicine has been applied should be 
avoided.  An alternative application site should be chosen. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy  
 
There are no adequate data from the use of fentanyl in pregnant women. Studies in animals have 
shown reproductive toxicity (see section 5.3). IONSYS should not be used in pregnancy unless clearly 
necessary. 
 
Administration during childbirth is not recommended because fentanyl crosses the placenta and the 
fetal respiratory centre is sensitive to opiates. If IONSYS is administered to the mother during this 
time, an antidote for the child should be readily available.  Following long-term treatment fentanyl 
may cause withdrawal symptoms in the newborn. 
 
Breast-feeding  
 
Fentanyl is excreted into human milk. Breast-feeding is not recommended for 24 hours following 
removal of IONSYS. 
 
Fertility  
 
There are no clinical data on the effects of fentanyl on fertility. Studies in rats have revealed reduced 
fertility and enhanced embryo mortality (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Opioid analgesics impair the mental and/or physical ability required for the performance of potentially 
dangerous tasks (e.g., driving a car or operating machinery). Patients should be advised not to drive or 
operate machinery if they experience somnolence, dizziness, or visual disturbance. 
 

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4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most commonly reported adverse reactions were nausea, vomiting, and application site reactions 
such as erythema and pruritus. These were mostly of mild to moderate severity.  The most serious 
adverse reactions reported were hypotension and apnoea and all patients should be closely monitored 
for these.  
 
Tabulated list of adverse reactions 
 
The following adverse reactions have been reported with IONSYS during clinical studies and post 
marketing experience. All adverse reactions are listed by System Organ Class and frequency: very 
common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); and rare (≥1/10,000 
to <1/1,000).  
 

System Organ Class Very Common Common  Uncommon Rare 

Infections and 
infestations 

   Rhinitis 

Blood and lymphatic 
system disorders 

    Anaemia  

Metabolism and nutrition 
disorders 

    Decreased 
appetite 

Hypocalcaemia 
Hypoglycaemia 
Hypokalaemia 

Psychiatric disorders   Insomnia Abnormal dreams  
Agitation 
Anxiety 
Confusional state 
Hallucination 
Nervousness 

Depression 
Thinking 
abnormal 
thoughts 

Nervous system disorders   Dizziness 
Headache 

Migraine 
Paraesthesia 
Somnolence  
Syncope 

Dysgeusia 
Hypoaesthesia 

Eye disorders     Vision blurred  
Ear and labyrinth 
disorders 

   Vertigo 

Cardiac disorders     Tachycardia Bradychardia 
Vascular disorders   Hypotension Hypertension 

Orthostatic 
hypotension, 
Vasodilitation 

 

Respiratory, thoracic and 
mediastinal disorders 

  Hypoxia Apnoea 
Cough  
Dyspnoea 
Hiccups 
Hypoventilation 

Lung disorder 

Gastrointestinal 
disorders 

Nausea 
Vomiting 

Constipation 
Abdominal pain 

Dry mouth 
Dyspepsia 
Flatulence 
Ileus 

Abdominal 
distension 
Diarrhoea 
Eructation 

Skin and subcutaneous 
tissue disorders 

 Pruritus Rash 
Hyperhidrosis 

 

Musculoskeletal and 
connective tissue 

  Back pain  
Pain in extremity 

Hypertonia 
Myalgia 

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System Organ Class Very Common Common  Uncommon Rare 

disorders 
Renal and urinary 
disorders 

 Urinary retention Oliguria Dysuria 

General disorders and 
administration site 
conditions 

Application site 
erythema 

Application site 
oedema 
Application site 
pruritus 
Application site 
reaction 
Application site 
vesicles  
Pyrexia 

Application site 
pain 
Application site 
dryness 
Application site 
papules  
Asthenia  
Chills  
Application site 
reaction 
Pain 

Chest pain  
Malaise 
Application site 
paraesthesia 
Injection site 
oedema 
Injection site pain 
Oedema 

Injury, poisoning and 
procedural complications 

   Wound 
complication 

Surgical and medical 
procedures 

  Gastrointestinal 
disorder therapy 

 

 
Paediatric population  
 
Data on IONSYS in paediatrics is limited to information from a single clinical trial. In this study 28 
paediatric patients, 6 to 16 years old, were treated with IONSYS fentanyl 40 micrograms after 
experiencing inadequate analgesia with IONSYS fentanyl 25 micrograms.  Among these patients, the 
incidence of nausea was similar to adult patients; however, vomiting (32.1%) and fever (60.7%) were 
each reported at a higher incidence in paediatric patients relative to adults. In summary, the limited 
size of the overall paediatric exposure is insufficient to guide safe and effective dosing of IONSYS in 
patients younger than 18 years of age. 
 
Elderly population 
 
Elderly patients (≥ 65 years) made up 28% (499/1763) of the total controlled clinical trial exposure to 
IONSYS 40 micrograms, with approximately 10% (174/1763) of exposures being in patients ≥ 75 
years. No overall differences were observed in the safety of IONSYS fentanyl 40 micrograms in 
elderly patients (≥ 65 years including a subpopulation ≥ 75 years) and adult patients for all controlled 
studies. Thus, the adverse reaction profile does not suggest a meaningful difference in safety compared 
to patients younger than 65 years of age. 
 
Obese patients 
 
In the controlled clinical trial population, the adverse reaction profile in patients with BMI > 40 
(86/1436 or 6%) showed no meaningful difference relative to patients with BMI ≤ 40. However, 
caution is recommended in these patients (see section 4.4).  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


11 

4.9 Overdose 
 
Symptoms  
 
The manifestations of fentanyl overdose are an extension of its pharmacologic actions, the most 
serious effect being respiratory depression (see section 5.2). 
 
Treatment  
 
For management of respiratory depression, immediate countermeasures include removing the 
IONSYS system and physically or verbally stimulating the patient. These actions can be followed by 
administration of a specific opioid antagonist such as naloxone, based on the clinical judgment of the 
treating health care professional. Respiratory depression following an overdose may outlast the 
duration of action of the opioid antagonist. The half-life of the antagonist may be short; therefore, 
repeated administration or infusion of the antagonist may be necessary. Reversal of the narcotic effect 
may also result in acute onset of pain and release of catecholamines.  
 
If the clinical situation warrants, a patent airway should be established and maintained, possibly with 
an oropharyngeal airway or endotracheal tube. Oxygen should be administered and respiration assisted 
or controlled, as appropriate. Adequate body temperature and fluid intake should also be maintained.  
 
If severe or persistent hypotension occurs, hypovolaemia should be considered and the condition 
should be managed with appropriate parenteral fluid therapy or other interventions as needed, based 
upon the clinical judgment of the treating health care professional. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Analgesics; phenylpiperidine derivatives; ATC code: N02AB03.  
 
Mechanism of action 
 
Fentanyl is an opioid analgesic, interacting predominantly with the opioid μ-receptor.  
 
Pharmacodynamic effects 
 
Its primary therapeutic actions are analgesia and sedation. Its secondary pharmacological effects are 
respiratory depression, bradycardia, hypothermia, constipation, miosis, physical dependence and 
euphoria (see section 5.2).  
 
Clinical efficacy and safety 
 
The efficacy and safety of IONSYS for treatment of acute, moderate to severe postoperative pain was 
evaluated in seven controlled studies in 1763 IONSYS patients: three placebo-controlled studies and 
four active-controlled studies. The placebo-controlled trials included 791 patients that were 
predominantly female (72%), Caucasian (82%), with a mean age of 45-54 years (range, 18-90 years), 
and primarily comprised of surgeries including lower abdominal (including pelvic) and orthopedic 
bone procedures. Patients were enrolled shortly after major surgery if they were not opioid tolerant, 
were expected to have an uncomplicated recovery, and required at least 24 hours of parenteral opioid 
treatment. Long-lasting or any non-opioid analgesics were not permitted. Patients were initially 
titrated to comfort with intravenous fentanyl or morphine, at which point they were randomized to 
IONSYS or a matching placebo system. During the first 3 hours post-enrollment, patients could 
supplement with bolus intravenous fentanyl given, as needed, to achieve comfort. After this point 727 
patients remained in the studies using only the IONSYS or control system, and were evaluated for 
efficacy. 

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The primary endpoint in each placebo-controlled study was the proportion of withdrawals due to 
inadequate analgesia during the period from 3 to 24-hours after IONSYS application. As illustrated in 
Table 1 below, IONSYS (fentanyl hydrochloride) was superior to placebo in all studies. Additional 
analyses suggest that the surgical procedure type did not influence the trends in efficacy endpoints and 
the efficacy of IONSYS was similar across the range of body mass indices studied (< 25 to > 40 kg/m2 
Body Mass Index). 
 

Table 1: Placebo-controlled Trials (N=727) Patients 
Percent (n) of patients who withdrew due to inadequate 

analgesia Hours 3-24 

Study IONSYS n=454 
Placebo 
n=273 p-value 

C-2001-011 27 % (64/235) 57 % (116/204) <0.0001 
C-2000-008 25 % (36/142) 40 % (19/47) 0.049 

C-95-016 8 % (6/77) 41 % (9/22) 0.0001 
 
IONSYS was also evaluated in four active-control trials (predominantly female (65%), Caucasian 
(85%), with a mean age of 55 years (range, 18-91 years), and primarily comprised of surgeries 
including lower abdominal and orthopedic bone procedures) using a standard intravenous patient 
controlled analgesia (PCA) morphine regimen as the comparator. In these studies, 1313 patients 
undergoing major surgery were randomized to PCA with intravenous morphine (1 mg morphine bolus, 
5 minute lock-out, total of 10 mg/h) delivered by a pump, and 1288 patients were randomized to 
IONSYS. Similar to the placebo-controlled studies, in the immediate postoperative period, patients 
were titrated to comfort with intravenous fentanyl or morphine per hospital protocol. Once 
comfortable, patients were then randomized to either IONSYS or intravenous PCA morphine 
treatment. Patients were instructed to use the system for pain relief. 
 
These studies evaluated IONSYS vs. intravenous PCA morphine in various surgical procedures 
commonly seen in clinical practice. Study C-2000-007 evaluated patients after undergoing abdominal, 
thoracic, or orthopedic surgeries; Study CAPSS-319 evaluated patients after undergoing total hip 
replacement; Study CAPSS-320 assessed IONSYS in patients following abdominal and pelvic 
surgeries; and Study FEN-PPA-401 assessed patients following major abdominal or orthopedic 
surgery. Patients could remain in their respective study up to 72 hours if they required parenteral 
opioid analgesia for this duration. A new IONSYS system was applied every 24 hours to different skin 
sites, or earlier if all doses were used. Supplemental intravenous opioid medication (fentanyl or 
morphine) was only allowed during the first 3 hours of IONSYS or PCA morphine treatment. 
Concomitant use of analgesics was not allowed after 3 hours in Studies C-2000-007 and CAPSS-320. 
In Study CAPSS-319, half the patients in each group received rofecoxib perioperatively and in Study 
FEN-PPA-401 patients were allowed non-opioid analgesics throughout the study period. The primary 
efficacy endpoint was the patient global assessment of method of pain control at 24 hours used to test 
equivalence between IONSYS and intravenous PCA morphine using a pre-specified ± 10% 
equivalence boundary with a 2-sided 95% confidence interval. Each patient and investigator was asked 
to rate the patient’s method of pain control as either poor, fair, good, or excellent. Efficacy results at 
the end of 24 hours, are presented in Table 2 below for the evaluable patient population. As shown 
below, the primary endpoint, proportion of patients reporting “Good or Excellent” ratings for the two 
methods of pain relief in all four studies demonstrated equivalence, with each 95% confidence interval 
contained within the prespecified ± 10% equivalence boundaries. 
 

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Table 2 
Active Comparator Trials (n=2569) Evaluable Patients 

 

Study No. 
IONSYS 
(fentanyl) 

n=1271 

IV-PCA 
(morphine) 

n=1298 
95% CIa, b 

Patient Global Assessment of Method of Pain Control -1st 24 
hour 

(% of patients rating good or excellent) 

C-2000-007 75%  (232/310) 
78% 

(246/316) 
 (-9.7%, 
3.7%)a, b 

CAPSS-319 84% (326/389) 
83% 

(331/397) 
 (-4.7%, 
5.6%)a, b 

CAPSS-320 86% (214/250) 
85% 

(212/251) 
 (-5.1%, 
7.4%)a, b 

FEN-PPA-
401 

87% 
(279/322) 

88% 
(293/334) 

 (-6.2%, 
4.0%)a, b 

a 95% Confidence Interval for difference in proportions 
b The pre-specified equivalence boundary was ± 10% 

 
Across the active-controlled studies, dosing with IONSYS was similar to intravenous PCA morphine 
pump use. The mean amount of supplemental opioid used during this time was also similar among 
patients treated with IONSYS or PCA morphine i.e. a range across the 4 studies of a mean dose of 5.0 
– 7.5 mg morphine in patients treated with IONSYS compared to a mean dose of 5.4 – 7.7mg 
morphine in patients receiving PCA morphine. . Patients who completed 24 hours of IONSYS 
treatment in the seven controlled studies used a wide range of the available 80 doses, with a mean of 
29.0 doses/patient (range of 0-93 doses) with the majority of patients (56.5%) using between 11 to 50 
doses. A single IONSYS system provided a sufficient number of doses for 99% of the studied patients 
over 24 hours. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
IONSYS in one or more subsets of the paediatric population for the treatment of acute pain. See 
section 4.2 for information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
At the initiation of each dose, an electrical current moves a pre-determined amount of fentanyl from 
the active substance-containing reservoir through the skin and into systemic circulation. IONSYS 
delivers a nominal dose of 40 micrograms fentanyl over each 10-minute dosing period at steady state.  
The mean systemic bioavailability is 87%. Upon system removal after the last dose, the decline in 
serum fentanyl concentration is similar to that of intravenous fentanyl. 
 
Absorption of fentanyl from IONSYS is similar whether applied to the upper outer arm or chest. When 
the system is applied on the lower inner arm, the amount of fentanyl absorbed is approximately 20% 
lower than at the upper outer arm or chest. Fentanyl pharmacokinetics are similar with both single and 
multiple 24 hour applications.  
 
Systemic absorption of fentanyl increases as a function of time independent of the frequency of 
dosing, with the initial dose being approximately 16 micrograms.  Steady state absorption of the 
nominal 40 microgram dose is achieved about 12 hours after application, indicating that the skin 
becomes more permeable to fentanyl during the first 12 hours.  The pharmacokinetic absorption 
profile will repeat with each application to a new skin site, therefore with each new application, 

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absorption will be lower initially. Consequently, the patient may activate IONSYS more frequently to 
maintain fentanyl blood levels. 
 
When IONSYS is applied without activating the electrical current, the average absorption rate of 
fentanyl over 24 hours was 2.3 micrograms fentanyl/hour, indicating minimal passive delivery.  
 
Average serum concentrations observed in post-surgical patients were in the range of 0.4-1.5 ng/ml 
over a 24 hour dosing period. In general, the maximum serum fentanyl concentration occurs 
approximately 15 minutes after the initiation of a dose.  
 
Following an on-demand dose of fentanyl by IONSYS, fentanyl has an absorption half-life of 
approximately 15 minutes.  
 
Distribution 
 
Fentanyl is highly lipophilic and is well distributed beyond the vascular system, with a large apparent 
volume of distribution. Fentanyl exhibits three compartment distribution pharmacokinetics. With 
intravenous administration, the initial distribution half-life is approximately 6 minutes; the second 
distribution half-life is 1 hour, and the terminal half-life is 13 hours. The plasma protein binding of 
fentanyl is 80% to 85%. The main binding protein is alpha-1-acid glycoprotein, but both albumin and 
lipoproteins contribute to some extent. The free fraction of fentanyl increases with acidosis. 
 
The average volume of distribution for fentanyl at steady state is 6 L/kg, the average clearance is 
53 L/h.  
 
Biotransformation 
 
Fentanyl is metabolised primarily in the liver to norfentanyl by CYP3A4 isoform. Norfentanyl is not 
pharmacologically active in animal studies. More than 90% of the administered dose of fentanyl is 
eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites. Skin does 
not appear to metabolise fentanyl delivered transdermally.  
 
Elimination 
 
Around 75% of fentanyl is excreted into the urine, mostly as metabolites, with less than 10% as 
unchanged active substance. About 9% of the dose is recovered in the faeces, primarily as metabolites. 
The total plasma clearance of fentanyl following intravenous administration is approximately 42 L/h 
 
Linearity/non-linearity 
 
Dose proportionality has been demonstrated from 25 to 60 micrograms per dose. 
None of the four demographic factors studied [weight (lean/obese), age, race, or gender] had a 
significant effect on active substance exposure (AUC) following use of IONSYS. 
 
Pharmacokinetic /pharmacodynamic relationship 
 
Minimum effective analgesic serum concentrations of fentanyl in opioid-naïve patients treated for 
acute post-operative pain range from 0.2 to 1.2 ng/ml; undesirable effects increase in frequency at 
serum levels above 2 ng/ml. 
 
Patients with genetic polymorphisms affecting CYP3A4 and CYP3A5  
 
Published literature has indicated that the CYP3A4*22 and CYP3A5*3 single nucleotide 
polymorphisms influence fentanyl to norfentanyl metabolism with the potential for increased fentanyl 
exposure in patients with these genetic polymorphs. Literature has shown that the genetic 
polymorphisms only account for a small amount of variability in concentrations of fentanyl with 
transdermal administration. Another published article of 52 elderly Japanese post-operative patients 

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receiving continuous intravenous (IV) fentanyl infusion (0.5-1.5 µg/kg/h) showed increased fentanyl 
exposure in the CYP3A5*3 group (3*/3*) than in the 1* carrier group. Clinical relevance is unknown 
from these published articles; however, caution should be used if administering IONSYS in patients 
with genetic polymorphisms of CYP3A4 and CYP3A5 (see section 4.4). 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose 
toxicity.  
 
Standard reproductive and developmental toxicity studies have been carried out using parenteral 
administration of fentanyl. In a rat study fentanyl did not influence male fertility. Studies with female 
rats revealed reduced fertility and enhanced embryo mortality.  
Effects on the embryo were due to maternal toxicity and not to direct effects of the substance on the 
developing embryo. There was no indication of teratogenic effects in studies in two species (rats and 
rabbits). In a study on pre- and postnatal development the survival rate of offspring was significantly 
reduced at doses which slightly reduced maternal weight. This effect could either be due to altered 
maternal care or a direct effect of fentanyl on the pups. Effects on somatic development and behaviour 
of the offspring were not observed.  
 
Mutagenicity testing in bacteria and in rodents yielded negative results. Fentanyl induced mutagenic 
effects in mammalian cells in vitro, comparable to other opioid analgesics. A mutagenic risk for the 
use of therapeutic doses seems unlikely since effects appeared only at high concentrations.  
 
A carcinogenicity study (daily subcutaneous injections of fentanyl hydrochloride for two years in 
Sprague Dawley rats) did not induce any findings indicative of oncogenic potential. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Bottom housing assembly:  
- bottom housing unit: glycol-modified polyethylene terephthalate  
- anode hydrogel:  polacrilin, purified water, sodium hydroxide, polyvinyl alcohol 
- cathode hydrogel:  purified water, sodium chloride, sodium citrate, polyvinyl alcohol, 

anhydrous citric acid, cetylpyridinium chloride 
- anode electrode:  layers of silver foil and electrically conductive adhesive tape 
- cathode electrode:  layers of polyisobutylene/silver chloride/carbon black composite material, 

silver foil, and electrically conductive adhesive tape 
- skin adhesive:  polybutene, polyisobutylene, and rosin ester  
- protective liner:  polyester film coated on one side with silicone. 
 
6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 
 
2 years 
Use immediately after opening. 
 
6.4 Special precautions for storage 
 
Do not store above 25°C.  
Do not refrigerate or freeze. 
 

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6.5 Nature and contents of container  
 
Each IONSYS system is packaged in a sealed thermoform tray. The tray contains one Controller and 
one sachet containing a Drug Unit.  The sachet foil is comprised of a lamination of nylon, aluminium 
foil and a heat seal layer of a copolymer of polyethylene and polymethacrylic acid.  
 
Each tray is packaged in a folding cardboard carton. There are 6 systems per carton. 
 
6.6 Special precautions for disposal and other handling 
 
Contact with the hydrogel can be harmful to humans. If the fentanyl hydrogel contacts the skin during 
application or removal, the area should be washed with copious amounts of water. Soap, alcohol, or 
other solvents should not be used to remove the hydrogel because they may enhance the active 
substances’ ability to penetrate the skin.  
  
Disposal  
 
The used IONSYS system contains a dangerous amount of fentanyl within the red hydrogel housing. 
Gloves must be worn when removing IONSYS from the patient’s skin and during disposal. The used 
system should be handled carefully by the sides and top. Contact with the hydrogel should be avoided. 
 
The design of the system allows separate disposal of the hydrogel housing and the Controller. 

 
To dispose of a used IONSYS system: 
 

1. Hold the Controller in one hand and pull the red tab with the other hand to separate the 
hydrogel housing from the system. 

 
2. Fold the hydrogel housing in half with the sticky side facing in.  

 
3. Dispose of the folded hydrogel housing in accordance with local requirements for opioid 

medicinal products.  
 

4. Dispose of remainder of the system, containing electronics, according to hospital procedures 
for battery waste.  

 
Local arrangements should be in place to ensure that used systems are returned appropriately (e.g., to 
hospital pharmacies) for disposal of the residual fentanyl in the hydrogel. Any unused medicinal 
product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Incline Therapeutics Europe Ltd 
21 St. Thomas Street 
Bristol 
BS1 6JS 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1050/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

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10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

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http://www.ema.europa.eu/


18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
Penn Pharmaceutical Services Ltd 
23-24 Tafarnaubach Industrial Estate 
Tredegar 
Gwent, South Wales 
NP22 3AA 
United Kingdom 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to special and restricted medical prescription (see Annex I: Summary of 
Product Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.  
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 
• Additional risk minimisation measures  

 
Prior to launch of IONSYS in each Member State the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational programme, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  
 
The MAH shall ensure that, following discussions and agreement with the National Competent 
Authorities in each Member State where IONSYS is launched all healthcare professionals who are 
expected to prescribe, dispense or administer IONSYS are informed through an information letter on 
having access to / are provided with the following items: 

• Summary of Product Characteristics (SmPC) and Package Leaflet 
• IONSYS Instructions for Use and Disposal  

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• Educational material (including prescriber checklist) for the healthcare professionals  
 

The Healthcare provider educational Programme shall contain the following key messages: 
• Information on the adequate use of the product with regards to medication errors (including 

accidental exposure), Device malfunction/failure, Product Disposal and 
Misuse/abuse/diversion/addiction and dependence.  

• Information highlighting that IONSYS is a patient-controlled device to be used in a 
hospital setting only and that standard practices for monitoring patients using such devices 
should be followed by healthcare professionals.  

• Information to aid healthcare professionals in selecting patients appropriate for treatment 
with IONSYS.  

• The importance of the healthcare professional ensuring that the patient understands how to 
operate the IONSYS system and that only he/she can press the dosing button during use.  

• The importance of reading the “IONSYS Instructions for Use and Disposal” including the 
troubleshooting guide and ensuring that the patient understands what to do in the event 
of a device failure/malfunction.  

• Checklist for monitoring inadequate product disposal to ensure healthcare professionals 
understand the dangers of inappropriate handling and accidental exposure to the IONSYS 
system.  

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21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IONSYS 40 micrograms per dose transdermal system  
Fentanyl 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 system contains fentanyl hydrochloride equivalent to 9.7 mg of fentanyl. 
1 system delivers 40 micrograms fentanyl per dose, to a maximum of 80 doses (3.2 mg/24 hours). 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: glycol-modified polyethylene terephthalate, purified water, sodium hydroxide, 
polacrilin, polyvinyl alcohol, trisodium citrate dihydrate, anhydrous citric acid, cetylpyridinium 
chloride monohydrate, sodium chloride, silver foil, electrically conductive adhesive tape (ECAT), 
polyisobutylene/silver chloride/carbon black, polyisobutene, polyisobutylene, rosin ester, siliconised 
polyester. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
6 transdermal systems 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Transdermal use 
Do not use if seal on the tray or the sachet containing the drug unit are broken or damaged. 
 

 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Use immediately after opening. 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Do not refrigerate or freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
A potentially dangerous amount of fentanyl remains in the system after use.  
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Incline Therapeutics Europe Ltd  
21 St. Thomas Street 
Bristol 
BS1 6JS 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1050/001 
  
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
TRAY LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
IONSYS 40 micrograms per dose transdermal system  
Fentanyl 
Transdermal use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
80 doses 
 
This tray contains: 
1 Drug Unit,  
1 Controller. 
 
 
6. OTHER 
 
Do not use if seal on the tray or the sachet containing the drug unit is broken or damaged. 
Do not store above 25°C. 
Do not refrigerate or freeze.  
See package leaflet for disposal information. 
 
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26 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHET LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
IONSYS 40 micrograms per dose transdermal system  
Fentanyl 
Transdermal use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
Use immediately after opening. 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
80 doses 
 
 
6. OTHER 
 
See package leaflet for disposal information. 
Tear at notch 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
IONSYS DEVICE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
IONSYS  
Fentanyl 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
 
 
4. BATCH NUMBER 
 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
 
6. OTHER 
 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the Patient 
 

IONSYS 40 micrograms per dose transdermal system 
fentanyl 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, please ask your doctor or your nurse. 
• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if 

their symptoms are the same as yours. 
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 

listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What IONSYS is and what it is used for 
2. Before you use IONSYS 
3. How to use IONSYS 
4. Possible side effects 
5. How to store IONSYS 
6. Contents of the pack and other information 
 
 
1. What IONSYS is and what it is used for 
 
What IONSYS is 
 
IONSYS is a transdermal system (to be applied on intact skin) that contains a strong analgesic (pain 
reliever) medicine called fentanyl. 
 
What IONSYS is used for 
 
IONSYS is used to treat short-term moderate to severe pain in adults after an operation. IONSYS is 
used in hospital only.  
 
How IONSYS works 
 
IONSYS is a small device applied to the skin of your upper arm or chest. It works by delivering 
fentanyl through your skin to relieve your pain.   
 
You must talk to a doctor if you do not feel better or if you feel worse. 
 
 
2. What you need to know before you use IONSYS 
 
Do not use IONSYS: 
• if you are allergic (hypersensitive) to fentanyl, or any of the other ingredients of IONSYS (listed 

in section 6). 
• if you suffer from severe breathing problems or cystic fibrosis.  
 
Warnings and precautions 
Talk to your doctor or nurse before using IONSYS if: 
• you have a severe or persistent lung disease, or any breathing problems 
• you have a very slow heart rate, low blood pressure, or other serious heart problem 
• you have problems with your liver or kidneys  
• you have severe headaches, have had a significant head injury, or have a brain tumour 

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• you have any difficulty hearing as you will need to be able to hear the device’s ‘beep(s)’ to know 
if it is working properly or if there is a problem  

• you have abnormally slow bowel movements or severe constipation 
• you have had a chest or upper abdominal operation  
• you are severely obese or have a condition called sleep apnoea that causes interrupted breathing 

during sleep and which can occur in severely obese individuals.  
 
Important things to be aware of 
IONSYS should be removed prior to certain procedures such as cardioversion (electrical current used 
to restore normal heart rhythm), defibrillation (electric shock given to the heart) or diathermy 
(electrical current used in physical therapy or surgery). IONSYS should also be removed prior to a 
magnetic resonance imaging (MRI) procedure, X-ray or CT scan. 
 
If you have a history of drug abuse, inform your doctor. 
 
If you have a genetic condition (polymorphism) which affects certain enzymes in your body (CYP3A4 
and CYP3A5), inform your doctor.   
 
If you  are an older patient your doctor will monitor you more carefully as IONSYS may affect you 
more than a younger patient. 
 
Children and adolescents  
IONSYS is not recommended for children and adolescents under 18 years of age due to the lack of 
data in these patients.   
 
Other medicines and IONSYS 
Tell your doctor or nurse if you are using, have recently used or might use any other medicines. Some 
medicines can affect the way IONSYS works, or make it more likely that you will have side effects. 
Tell your doctor or nurse if: 

• you are taking medicines that might make you sleepy such as sleeping tablets, tranquilisers, 
medicines for anxiety or medicines for allergies (anti-histamines); 

• you are taking muscle relaxants (prescribed for back pain), or if you are undergoing general 
anaesthesia; 

• you are taking medicines for HIV infection (such as ritonavir, nelfinavir, amprenavir or 
fosamprenavir); 

• you are taking medicines for fungal infections (such as ketoconazole, itraconazole or 
fluconazole); 

• you are taking medicines for bacterial infections (such as troleandomycin, clarithromycin or 
erythromycin); 

• you are taking medicines used to help treat nausea and vomiting (such as aprepitant); 
• you are taking medicines used for high blood pressure or heart problems (such as diltiazem 

and verapamil); 
• you are taking pain killers called partial agonists like buprenorphine, nalbuphine, pentazocine; 
• you are taking medicines for depression called monoamine-oxidase (MAO) inhibitors.  Tell 

your doctor or nurse if you have taken them within the last 14 days before using IONSYS; 
• you are using medicines for topical use (i.e. medicines that are applied on the skin).   

 
IONSYS with food, drink and alcohol 
Do not drink alcohol or grapefruit juice whilst you are wearing IONSYS because it can increase the 
risk of experiencing dangerous side effects. 
 
Pregnancy and breast-feeding 
You must tell your doctor before using IONSYS if you are pregnant or planning to become pregnant. 
Your doctor will discuss the possible risks and potential benefits of using IONSYS while you are 
pregnant. 

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IONSYS should not be administered during childbirth. If you are given IONSYS during childbirth 
your baby may need to be given an antidote when it is born. Prolonged treatment with fentanyl, the 
active substance in IONSYS, may cause withdrawal symptoms in the newborn baby. 
 
Do not use IONSYS if you are breast-feeding. Fentanyl can pass into the breast milk and may cause 
side effects to the breast-fed child. You should not start breast-feeding until the IONSYS system has 
been removed for 24 hours. 
 
Driving and using machines 
IONSYS may make you feel sleepy, dizzy or cause blurred vision. Do not drive, operate machines or 
power tools when you leave hospital if you experience any of these side effects. 
 
 
3. How to use IONSYS 
 
Always use this medicine exactly as your doctor or nurse has told you. Check with your doctor or 
nurse if you are not sure about how to use IONSYS or forget your instructions.  
 
The recommended dose 
Each dose of IONSYS delivers 40 micrograms of fentanyl.  
 
You control your own treatment under the guidance of your doctor or nurse in hospital. IONSYS only 
delivers the medicine when you activate it, so you control how much medicine you receive.  You can 
take a dose whenever you need it for your pain, or just before you do an activity that may increase 
your pain (such as physical therapy, getting out of bed, etc.). Each time you are given a new IONSYS 
you may find you initially need to have more doses to relieve your pain than later on during treatment. 
 
Duration of treatment 
Each IONSYS works for one day (24 hours) and contains 80 doses.  IONSYS will stop working after 
one day (24 hours) or after 80 doses have been delivered, whichever one comes first.  The green light 
will switch off and the number of doses delivered will flash on and off.  No more doses can be 
delivered after this and IONSYS will be removed by your doctor or nurse. 
 
Your doctor or nurse will remove the IONSYS system before you leave hospital.  After IONSYS has 
been removed, it may leave small reddish marks at the skin site.  This is common, and nothing to 
worry about.  The red area will fade over the next few days to a week. 
 
Using IONSYS 

• Do not let your family or friends start IONSYS for you. Only you know how much pain 
you are having, and only you should operate IONSYS to start a dose of medicine. To make 
sure you get the correct amount of medicine, press IONSYS as soon as you start to feel pain.  

• Do not touch the sticky side of IONSYS.  This side of the system contains material called 
“gels” which you should not normally come into contact with.  Swallowing or touching these 
gels may cause life-threatening breathing difficulties or death, even after you have stopped 
using the system and it has been removed.  Do not let these touch your mouth or eyes. 

• If you do accidentally touch the gels on the underside of the system: 
- Alert a nurse or doctor right away 
- Rinse your hands with large amounts of water 
- Do not use soap, alcohol, or other solvents to remove the gels because they may 

increase the medicine’s ability to go through the skin. 
• The doctor or nurse will put IONSYS on your skin, and take it off or replace it when needed. 

Only let the doctor or nurse place or remove IONSYS. 
- Do not take it off or attempt to put it back on yourself. 
- Do not let the IONSYS system get wet because it could stop working or fall off.  

 

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How to use IONSYS 
 

• The doctor or nurse will get IONSYS ready to use and attach it 
to your upper outer arm or chest. 

• The slow blinking green light means IONSYS is ready to 
dose. 

• To start a dose from IONSYS, press and release the dosing 
button twice within 3 seconds.  You will know you have 
started a dose when you hear a beep. 
- You will know the dose is being delivered when the 

green light blinks faster. 
• Each dose will last for 10 minutes.  IONSYS will ignore 

additional button presses during this 10-minute dosing period. 
• You will know the 10-minute dosing period is complete when 

the fast blinking green light becomes slow again.  The 
digital display will show the number of doses that have been 
delivered. 

• IONSYS is ready to be used again and you may start another 
dose at any time you need it. However, only press the button 
when you need pain relief.  

 

 
You will hear IONSYS beep once each time you start a dose.  If it beeps at any other time, or more 
than once, tell your doctor or nurse immediately.  They will check that IONSYS is working properly. 
 
If you use more IONSYS than you should 
IONSYS is designed so that you can’t use too much, provided that only you operate it, and that only 
you use it when you need pain relief.  
 
If you do use more IONSYS than you should then you may experience shortness of breath, difficulty 
breathing, rapid and shallow breathing, or feeling faint. If you experience any of these symptoms then 
tell your doctor or nurse immediately. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
If you feel faint or if you have difficulty in breathing while being treated with IONSYS, tell a 
doctor or nurse immediately. 
The following side effects may occur whilst using IONSYS: 
 
Very common (may affect more than 1 in 10 people) 

• feeling sick (nausea) or being sick (vomiting) 
• reddening of skin at the patch site 

 
Common (may affect up to 1 in 10 people) 

• dizziness 
• headache 
• itching skin 
• low blood pressure 
• difficulty sleeping 
• constipation, stomach pain 
• blue skin colour (lips and finger tips) 
• swelling, itching, irritation or blistering of skin at the patch site 
• inability to pass water (urinate) 

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33 

• fever  
 

Uncommon (may affect up to 1 in 100 people) 
• flushing 
• anaemia (low blood count) 
• decreased appetite 
• anxiety 
• abnormal dreams or hallucinations (seeing or hearing things that are not there) 
• feeling confused or agitated 
• severe headache (migraine) 
• nervousness 
• pins and needles sensation 
• sleepiness 
• blurred vision 
• looking pale, feeling low in energy or tired 
• fast or irregular heartbeat 
• shortness of breath or interruptions in breathing 
• cough, hiccups 
• rash 
• excessive sweating 
• fainting 
• dry mouth 
• passing water (urinating) less frequently than normal 
• indigestion 
• passing wind, difficulty passing stools 
• chills 
• back pain, pain in arms or legs 
• pain, bumps, or dry skin at the patch site 
• high blood pressure 
• fall in blood pressure when standing up 
• decreased bowel activity 
• slow breathing rate 
• body pain 

 
Rare (may affect up to 1 in 1,000 people) 

• sneezing, itchiness and blocked or runny nose 
• low calcium/glucose/potassium in blood serum 
• depression, abnormal thoughts 
• abnormal sense of taste 
• reduced sense of touch or sensation 
• vertigo 
• slow heart beat 
• lung disease 
• swelling of the abdomen, diarrhoea, burping/belching 
• tightness/tension in muscles, muscle pain 
• pain when urinating 
• chest pain, feeling of general discomfort or uneasiness 
• tingling, prickling, swelling or pain at site of IONSYS application 
• complications in wound healing 
• fluid retention/swelling in the body 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

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34 

Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store IONSYS 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton, or tray or sachet label, 
after “EXP”.  The expiry date refers to the last day of that month. 
 
Do not store above 25°C. 
 
Do not refrigerate or freeze. 
 
The hospital staff will store IONSYS. The used IONSYS will be disposed of by medical staff. 
 
 
6. Contents of the pack and other information 
 
What IONSYS contains 
The active substance in IONSYS is fentanyl hydrochloride. Each IONSYS system contains fentanyl 
hydrochloride equivalent to 9.7 mg of fentanyl and delivers 40 micrograms fentanyl per dose, to a 
maximum of 80 doses (3.2 mg/24 hours). 
 
The other ingredients are:   
bottom housing unit: glycol-modified polyethylene terephthalate  
anode hydrogel:  polacrilin, purified water, sodium hydroxide, polyvinyl alcohol 
cathode hydrogel:  purified water, sodium chloride, sodium citrate, polyvinyl alcohol, anhydrous citric 
acid, cetylpyridinium chloride 
anode electrode:  layers of silver foil and electrically conductive adhesive tape 
cathode electrode:  layers of polyisobutylene/silver chloride/carbon black composite material, silver 
foil, and electrically conductive adhesive tape 
skin adhesive:  polybutene, polyisobutylene, and rosin ester  
protective liner:  polyester film coated on one side with silicone. 
 
What IONSYS looks like and contents of the pack 
IONSYS is a transdermal system and is made up of an electronic controller (the top housing) and a 
drug unit (the red bottom housing). The controller is made of white plastic with the identifier 
“IONSYS” and has a digital display, a light window, and a dosing button. The drug unit is blue on the 
side that connects to the controller and has a red bottom housing containing the hydrogels, one of 
which contains the fentanyl hydrochloride. 
 
Each IONSYS carton contains 6 systems.   
 
Marketing Authorisation Holder 
Incline Therapeutics Europe Ltd  
21 St. Thomas Street 
Bristol 
BS1 6JS 
United Kingdom 
 
Tel: +44 (0)800 587 4149 or +44 (0)203 684 6344 
Email: medical.information@themedco.com 
 
Manufacturer 
Penn Pharmaceutical Services Ltd 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


35 

23-24 Tafarnaubach Industrial Estate 
Tredegar 
Gwent, South Wales 
NP22 3AA 
United Kingdom 
 
This leaflet was last revised in MM/YYYY 
 
Other sources of information  
Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.ema.europa.eu/. 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
Information for the Healthcare Professional: 
Instructions for use and disposal  

 
 

 
 

 
IONSYS (fentanyl 40 micrograms per dose transdermal system, 
maximum of 80 doses (3.2 mg/24 hours)). 
 
For single use only. 
 
IONSYS should not be used if the seal on the tray or the sachet 
containing the drug unit is broken or damaged. 
 
IONSYS will operate for 24 hours after it is applied or for 80 
doses, whichever comes first, and will then become inoperative. 
 
Refer to the Summary of Product of Characteristics (SmPC) for 
more information about IONSYS. 
 

 
 
 
 

 
 
 
 
 

 

1. Preparation of the Application Site 
 
• Only 1 IONSYS system should be applied at any given time.  
 
• Choose healthy, unbroken skin (non-irritated and non-

irradiated skin) site on the chest or upper outer arm ONLY.  
IONSYS should not be placed on abnormal skin sites, such as 
scars, burns, and tattoos, or on skin on which topical medicines 
have been applied. 
 

• Excessive hair at the application site should be clipped (not 
shaved as this can irritate the skin) before application.  
IONSYS should not be applied to a previously used skin site. 

 
• The application site should be wiped with a standard alcohol 

swab and the skin should be allowed to dry completely before 
IONSYS is applied.  No soaps, oils, lotions, or any other 
agents that might irritate the skin or alter its absorption 
characteristics, should be used to clean the application site. 

 
• When replacing an IONSYS system, the new system must be 

applied to a different site on the chest or upper outer arm.  
 

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http://www.ema.europa.eu/


36 

 
 
 
 

 
 

 
 

 
 

 
 

 
 

2. Assembly of IONSYS 
 
Complete these steps before applying IONSYS to the patient: 
 
• Gloves should be worn during the assembly/handling of 

IONSYS. Open the tray by peeling back the tray lid.  Remove 
the sachet and the controller.  Open the sachet containing the 
drug unit starting at the pre-cut notch and then carefully 
tearing along the top of the sachet. 

 
 
 
 
• Remove the drug unit from the sachet and place on a hard, flat 

surface. 
 
 
 
 
 
 
 
• Align the matching shapes of the controller and the drug unit 

and firmly press the two parts together at both ends. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Once assembled, the digital display of the controller will 

complete a short self-test during which there will an audible 
beep, the red light will flash 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 flash at a slow 
rate to indicate IONSYS is ready for application. 

 

 

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37 

 
 
 

 
 

 
 

3. Application of IONSYS 
 

• Remove and discard the clear plastic liner covering the 
adhesive. Take care not to touch the hydrogels. 

 
 
 
 
 
 
 
• Press IONSYS firmly in place for at least 15 seconds with the 

sticky side down on the skin of the chest or upper arm of the 
patient.  Apply pressure with the fingers around the outer 
edges to ensure adhesion to the skin site. Do not press the 
dosing button.  

 
• If at any point during use IONSYS loosens from the skin, a 

non-allergenic tape may be used to secure the edges to ensure 
complete contact with the skin.  When applying tape, care 
should be taken not to tape over the light window, the digital 
display, or the dosing button.  

 
• Each IONSYS may be used for 24 hours from the time of 

assembly or until 80 doses have been administered, whichever 
comes first.  IONSYS will then shut down and will not deliver 
any further doses.  If additional opioid analgesia is required, a 
new IONSYS should be applied to a different skin site, after 
removal and disposal of the previous IONSYS. 

 
• Patients should not wear more than one IONSYS at the same 

time.  A used IONSYS should not be reapplied to patients. 
 

 

 

4. Instructing the patient how to use IONSYS 
 

Remember that only the patient may touch the dosing button.  
Tell your patient the following: 
 
• The slow blinking green light means IONSYS is ready to 

dose. 
 

• To start a dose, press and release the dosing button 2 times 
within 3 seconds.  You will hear one single beep upon 
successful dose initiation. 
 

• You will know the dose is being delivered when you see the 
fast blinking green light. 
 

• IONSYS will ignore any button presses during the 10-minute 
dosing period. 
 

• You will know the 10-minute dose is complete when the fast 
blinking green light returns to a slow blinking green light. 
 

• Call your doctor or nurse if you hear additional beeps. 

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38 

 
 
 
 
 
 

 
 

 
 

 
 

5. Removal and disposal of IONSYS  
 
See also instructions in SmPC Section 6.6. 
 
• Gloves must be worn while removing IONSYS from the skin 

and care should be taken to avoid touching the hydrogels.  If 
the fentanyl hydrogel contacts the skin during removal, the 
contact area should be thoroughly rinsed with water without 
using any soap. 

 
• IONSYS may be removed at any time.  However, once it has 

been removed, the same IONSYS should not be reapplied.  
 

• At the end of 24 hours of use, or after 80 doses have been 
delivered, remove IONSYS by gently lifting the red tab and 
loosening it from the skin application site.  If the patient 
requires additional or continuation of pain relief, a new 
IONSYS may be applied to a new skin site on the upper outer 
arm or chest.  

 
• Hold the controller in one hand and pull the red tab with the 

other hand to separate the hydrogel housing from the system. 
 

• Fold the hydrogel housing in half with the sticky side facing 
in. 

 
• Dispose of the folded hydrogel housing in accordance with 

local requirements for opioid medicinal products 
 

• Dispose of remainder of the system, containing electronics, 
according to hospital procedures for battery waste. 

 

 
IONSYS Troubleshooting 
Each IONSYS is designed to deliver up to 80 10-minute doses of fentanyl over a period of 24 hours.  
The table below represents the different error messages that may occur, together with the probable 
cause and the action to be taken. 
 

Error message/feedback Probable cause Action required 
 

 
 

Low battery or defective 
system 

1. Do not use the system. 
2. Dispose of system per above Step 5 - 

Removal and Disposal of IONSYS. 
3. Place a new system on a different skin site. 
 
 

 Poor skin contact 1. If IONSYS appears to be loose or lifting 
from the skin, secure it to patient’s skin by 
pressing the edges firmly or by applying 
non-allergenic tape. 

2. If using tape, apply it along the edges of 
IONSYS system, do not cover the dosing 
button or display.  

3. If system beeps again, then remove and 

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39 

 
 

dispose of system, and place a new system 
on a different skin site.  

 

 

 
 

System error 1. Remove system from patient. 
2. Hold down dosing button until beeping 

stops and display goes blank. 
3. Dispose of system per above Step 5 - 

Removal and Disposal of IONSYS. 
4. Place a new system on a different skin site. 
 

 

 
 

End of use at 24 hours or 
80 doses 

1. Remove system from patient. 
2. Hold down dosing button until display 

goes blank. 
3. Dispose of system per above Step 5 - 

Removal and Disposal of IONSYS. 
4. Place a new system on a different skin site. 
 

 
 
If device failure or malfunction is suspected by a healthcare professional, IONSYS should be 
immediately removed from the patient and The Medicines Company contacted straightaway.  
The healthcare professional must ensure the patient understands that if they suspect a device failure or 
malfunction, they must inform a healthcare professional immediately. 
 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET