The legally binding text is the original French version TRANSPARENCY COMMITTEE. Opinion. 18 October 2006

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE Opinion 18 October 2006 IONSYS 40 microgrammes per dose, iontophoretic transdermal system. Box containing 1 system: Applicant: JANSSEN-CILAG Fentanyl Narcotic Medicinal product for hospital use only Date of Marketing Authorisation: 24 January 2006 Reason for request: Inclusion on the list of medicines approved for use by hospitals Health Technology Assessment Division 1

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Fentanyl Each IONSYS system contains 10.8 mg of fentanyl hydrochloride equivalent to 9.7 mg of fentanyl and delivers 40 microgrammes of fentanyl per dose, up to a maximum of 3.2 mg (80 doses) 1.2. Background This is the first iontophoretic system containing fentanyl using the transdermal administration route. This controlled analgesia is introduced only once the patient's pain has been brought under control by means of intravenous opioids Indication IONSYS is indicated for the treatment of acute moderate to severe post-operative pain exclusively in a hospital setting Dosage IONSYS should be restricted to hospital use only. Due to the well known potential of abuse of fentanyl physicians should evaluate patients for a history of drug abuse. Special precautions for disposal should be followed. IONSYS should only be activated by the patient. Before any surgery, the healthcare professional should ensure that the patient has been properly informed on how to use IONSYS post-operatively. IONSYS delivers 40 micrograms per on-demand dose up to a maximum of 240 micrograms (6 doses each of 10 minutes duration) per hour but not more than a maximum of 80 doses within a 24 hour period. Patients should be titrated to an acceptable level of analgesia prior to initiating use of IONSYS. The system should only be activated by the patient in response to pain. IONSYS will operate for 24 hours following completion of the first dose or for 80 doses, whichever comes first, and then becomes inoperative. If the patient attempts to initiate a dose after 80 doses or 24 hours from the first dose, the system will not respond (i.e. no red light, no beep). The maximum treatment duration is 72 hours (3 systems), although the majority of patients should only need one system. Patients should not wear more than one system at a time. Used systems should not be reapplied to a patient. Patients should not get the IONSYS system wet. Prolonged contact with water could affect system performance and cause the system to malfunction or fall off. IONSYS should be removed before the patient is discharged. Children and adolescents IONSYS is not recommended for use in children below age 18 years due to insufficient data on safety and efficacy. 2

3 Elderly Limited data on pharmacokinetics, safety and efficacy are available for the use of IONSYS in patients >75 years. Elderly patients should be observed carefully for signs of fentanyl toxicity. IONSYS Testing Instructions for the Pharmacist or Other Health Care Professional (To be Performed Prior to Dispensing): Please refer to section 6.6 of the SPC. Method of Application The IONSYS system should not be used if the seal on the sachet is broken. IONSYS should be applied to intact, non-irritated and non-irradiated skin on the chest or upper outer arm. IONSYS should not be placed on abnormal skin sites, such as scars, burns, tattoos, etc. 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, the skin allowed to dry completely before the IONSYS system is applied. No soaps, oils, lotions, or any other agents that might irritate the skin or alter its absorption characteristics, should be used. The sachet containing IONSYS should be opened starting at the pre-cut notch, then by carefully tearing along the top of the sachet. The system should be removed from the sachet and used immediately. The moisture absorber should be discarded after opening the sachet. If no moisture absorber is present, or if the moisture absorber is not intact, do not use and return system to manufacturer. The clear plastic liner covering the adhesive should be removed and discarded with care taken not to touch the gels. The IONSYS system should be pressed firmly in place with the sticky side down on the skin for at least 15 seconds. Pressure should be applied with the fingers around the outer edges to ensure adhesion to the skin site for the full 24-hour wearing period. Occasionally, the IONSYS system may loosen; if this occurs a non-allergenic tape may be used to be sure all of the system s edges make complete contact with the skin. Care should be taken not to press or tape over the button or red light. 3

4 Dose Delivery A recessed on-demand dosing button and red light are located on the top housing of the IONSYS system. To initiate administration of a fentanyl dose, the patient should press the on-demand button twice within 3 seconds. IONSYS should only be activated by the patient. A beep indicates the start of delivery of the dose; the red light remains on throughout the 10- minute dosing interval. The next dose cannot be initiated until the previous 10-minute delivery cycle is complete. Pressing the button during delivery of a dose will not result in additional medicinal product being administered. The red light turns off after the 10-minute dose has been delivered. Determining Approximate Number of Doses Delivered Between doses, the red light will blink in one-second pulses to indicate the approximate number of doses administered up to the present time. Each one-second pulse of light indicates administration of up to five doses. Thus, a single one-second pulse of light represents 1 to 5 doses; two pulses represent 6-10 doses; three pulses represent doses; up to 16 pulses which represents doses delivered. The system may also be queried during delivery of an on-demand dose by pressing the button once. The red LED will pulse as outlined above to indicate the approximate number of on-demand doses delivered up to the query. This query will not influence dose delivery. Removal IONSYS may be removed at any time. However, once a system has been removed, the same system should not be reapplied. At the end of 24 hours of use or after 80 doses have been delivered, remove the IONSYS system by gently lifting the red tab and loosening the system from the skin application site. If the patient requires additional or continuation of pain relief, a new system may be applied to a new skin site on the upper outer arm or chest. Troubleshooting Each IONSYS system is designed to deliver every on-demand dose of fentanyl over approximately 10 minutes. If a technical failure with a system is suspected, the staff member or patient should monitor both the illumination of the red LED and any audible signals (beeps) over the next dose. The table below represents the different error messages that may occur, together with the appropriate action to be taken: Error Message Frequency 2 beeps repeated 8 times (approximately 15 seconds) and red LED turns off before 10 minutes 4 continuous beeps and red LED turns off before 10 minutes Red LED fails to illuminate Action Up to 2 more attempts may be made to request new delivery. If all attempts fail, the system should be removed and a new system applied to a new skin site. The system cannot be restarted. It should be removed and a new system applied to a new skin site. The system should be removed and a new system applied to a new skin site. 4

5 2 COMPARABLE MEDICINAL PRODUCTS 2.1. ATC classification (2005) N : Nervous system 02 : Analgesics A : Opioids B : Phenylpiperidine derivatives 03 : Fentanyl 2.2. Medicines in the same therapeutic category All fentanyl-based proprietary products indicated in the treatment of pain: ACTIQ, tablets with mouth applicator, DUROGESIC transdermal patches, FENTANYL DAKOTA PHARM, solution for injection FENTANYL JANSSEN, solution for injection FENTANYL MERCK, solution for injection FENTANYL PANPHARMA, solution for injection FENTANYL QUALIMED, solution for injection FENTANYL RENAUDIN, solution for injection 2.3. Medicines with a same therapeutic aim Analgesics on step III of the WHO ladder. 3 ANALYSIS OF AVAILABLE DATA The efficacy and tolerance of IONSYS used to control post-operative pain have been established on the basis of: - Three controlled, randomised, double-blind, phase III clinical trials versus placebo (C , C , C ) conducted on 791 patients for the control of acute moderate to severe post-operative pain. - One randomised, open-label, phase III non-inferiority clinical trial (C ) versus patient-controlled intravenous morphine analgesia (IV PCA). - Three randomised, open-label, phase III non-inferiority trials (FEN-PPA-401, CAPSS- 319 and CAPSS-320) versus patient-controlled intravenous morphine analgesia; these trials will not be discussed in detail below as they have not been submitted to the Marketing Authorisation (MA) authorities. 5

6 3.1. Efficacy Studies versus placebo The three studies versus placebo (C , C and C ) had identical protocols: randomised double-blind studies comparing the efficacy of IONSYS with that of a placebo in patients who had undergone thoracic surgery, orthopaedic surgery or abdominal surgery and who were likely to experience acute moderate to severe pain requiring parenteral administration of morphinomimetics for at least 24 hours after surgery. The patients had to have baseline pain levels above five on a visual scale from zero (no pain) to ten (worst pain imaginable). The patients were given the following substances for self-administration for up to 24 hours: either - IONSYS 40 µg/dose on demand every 10 minutes up to a maximum of six doses per hour (80 doses) - or a placebo Primary endpoint: Number of patients who could be assessed withdrawn from the study because of inadequate pain control during the 24-hour treatment period. One patient who could be assessed was defined in the protocol as having had at least three hours treatment with IONSYS, as intravenous fentanyl administration was permitted during the first three hours. C of the 205 randomised patients underwent treatment for over three hours and were included in the analysis. Results: IONSYS placebo p Patients (N) Withdrawn from the study because 36 (25.4%) 19 (40.4%) of inadequate pain control Average length of treatment in hours 6.5 ± ± 1.17 Intensity of pain after 24 hours on the visual analogue scale from 1 to 100 mm 30.9 ± ± In the population of patients who could be assessed, the number of patients withdrawn from the study because of inadequate pain control after the first three hours of treatment was statistically lower in the IONSYS group (25.4%) than in the placebo group (40.4%). However, this difference was not significant for all the randomised patients. One patient used more than one IONSYS system (80 doses). Tolerance: Nausea (31.2% versus 25.5%), vomiting (11.7 % versus 5.9%) and pruritis (7.1% versus 0%) were more frequent in the IONSYS group than in the placebo group. 1 Chelly JE, Grass J, Houseman TW, Minkowitz H, Pue A. The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebocontrolled trial. Anesth Analg Feb;98(2):

7 Four patients receiving fentanyl were withdrawn from the study because of nausea. 35.7% of the patients in the IONSYS group had visible erythema when the system was removed compared to 13.8% in the placebo group. C Results: 439 of the 484 randomised patients continued with the study for over three hours of treatment and were included in the analysis. Results: IONSYS placebo p Patients (N) withdrawn from the study because of inadequate pain control 64 (27.2%) 116 (56.9 %) < Average length of treatment (in 7.8 ± ±0.48 hours) Intensity of pain after 24 hours on the visual analogue scale from 1 to The percentage of patients withdrawn from the study because of inadequate pain control after the first three hours of treatment was significantly lower in the IONSYS group than in the placebo group (27.2% versus 56.9%). Four patients used more than one IONSYS system (80 doses). N.B.: According to the CHMP (Committee for Human Medicinal Products), excluding patients who had been treated for less than three hours from analysis introduced a bias into the main analysis. Tolerance: The proportion of patients withdrawn from the study because of adverse events (nausea, confusion, pruritis and insomnia) was 2.5% in the IONSYS group and 1.3% in the placebo group. C This single-centre study conducted on 102 patients will not be discussed in detail as its protocol is identical to that of the two other studies conducted versus placebo. The results did not deviate from those of the two preceeding studies: the percentage of patients withdrawn from the study because of inadequate pain control after the first three hours of treatment was significantly lower in the IONSYS group (7.8%) than in the placebo group (40.9%) Studies versus an active reference substance Four open-label, non-inferiority, randomised studies (FEN-PPA-401, C , CPASS- 319 and CAPSS-320) compared treatment with IONSYS to intravenous patient-controlled morphine analgesia (IV PCA) in patients likely to suffer from acute moderate to severe postoperative pain for 72 hours after surgery. 2 Viscusi ER, Reynolds L, Tait S. An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain : A double-blind, placebo-controlled trial, Anesth Analg 2006 ; Study being prepared for publication 7

8 Patients were allowed to use emergency pain relief in the first three hours of treatment. C Primary endpoint: Overall assessment of pain control by the patient 24 hours after the start of treatment ("What is your overall assessment of this method of pain control during the last 24 hours of treatment: poor, moderate, good or excellent? ), measured by the percentage of patients who could be assessed who were successfully treated 4, 24 hours after the start of treatment. One patient who could be assessed was defined in the protocol as having had at least three hours treatment with IONSYS, as intravenous fentanyl or morphine administration was permitted during the first three hours. Treatment with IONSYS was regarded as no inferior to IV PCA morphine treatment if the 95% confidence interval of the difference in the success rates of the two treatments was less than 10%. The patients had undergone thoracic surgery, orthopaedic surgery or major abdominal surgery. They were included in the study if their pain score was <50 mm on the analogue visual scale (VAS). They were given the following substances for self-administration for at least 24 hours: - Either IONSYS 40 µg/dose on demand every 10 minutes up to a maximum of six doses per hour (80 doses); - Or 1 mg of morphine in an IV bolus administration on demand every five minutes up to a maximum of 10 mg/hour. Results: 626 of the 636 randomised patients underwent treatment for more than three hours and were included in the analysis. Overall assessment of pain control by the patient 24 hours after the start of treatment. IONSYS IV PCA morphine p Patients who could be assessed Patients who were successfully treated (%) 232 (74.8%) 246 (77.8%) Excellent 122 (39.4%) 108 (34.2%) Good 110 (35.5%) 138 (43.7%) 0,376 95% CI [-9.7%; 3.7%] IONSYS was shown not to be inferior to IV PCA morphine in terms of the percentage of patients successfully treated 24 hours after the start of treatment. It should be noted that this was an open-label study.the choice of primary endpoint (question as to the patient's or investigator's preference) is open to debate, bearing in mind that no data is available on how the VAS was assessed during treatment or on the time until pain relief was achieved. 4 Treatment was regarded as "successful" when the patient's assessment of the method of pain control was rated as good or excellent. 8

9 No significant difference between the two groups was observed on the final assessment of the pain intensity score after 24 hours: 32.7 ± 1.6 for the IONSYS group and 31.1 ± 1.5 for the IV PCA morphine group, p=0.45. Tolerance: The most frequent adverse events were those known to be associated with opioids (nausea, vomiting) and pruritis; there was no difference in incidence between the two groups. One patient in the IONSYS group developed severe confusion and one patient in the morphine IV group developed respiratory depression. It is difficult to establish an objective comparison between the two forms of treatment because of the design of the study (open-label). 7% of the patients in the IONSYS group experienced a reaction at the application site. Three other non-inferiority studies versus patient-controlled morphine perfusion (FEN-PPA- 401, CAPSS-319 et CAPSS-320) are available. These studies, which have not been assessed by the Marketing Authorisation authorities, confirm that IONSYS is no inferior to IV PCA morphine Adverse effects In the three studies versus placebo, the most frequent adverse events in patients taking IONSYS or placebo were as follows: nausea (37.9% versus 21.2%), erythema at the application site (14.1% versus 2.2%), vomiting (11.8% versus 5.7%), fever (8.6% versus 10.4%) and headache (8.6% versus 6.6%). The tolerance of IONSYS 40 microgrammes was assessed on a total of 791 patients during controlled clinical trials. The most frequently reported adverse events were nausea, vomiting, headache and pruritis, generally of low to moderate intensity. Slight to moderate reactions at the application site were observed in less than 7% of patients being treated with IONSYS. Erythema was observed in 53.8% of patients being treated with IONSYS 24 hours after removal of the system. The studies took place over a too short period to allow assessment of the time taken for lesions to disappear and of whether there were any lasting effects on the skin Conclusion In two randomised studies versus placebo (C and C ) the number of patients who could be assessed who stopped the protocol because of inadequate pain control after the first three hours of treatment was statistically lower in the IONSYS group (25.4% to 27.2% depending on the studies) than in the placebo group (40.4% to 56.9%). However, in the C study this difference was not significant for all randomised patients. According to the CHMP, exclusions within three hours in the C study introduced a bias into the main statistical analysis. An open-label non-inferiority study (C , non-inferiority threshold of -10%) showed that IONSYS was non inferior to IV PCA morphine. The percentage of patients successfully 9

10 treated 24 hours after the start of treatment was 74.8% for IONSYS and 77.8% for IV PCA morphine. It should be noted that this was an open-label study.the choice of primary endpoint (question as to the patient's or investigator's preference) is open to debate, bearing in mind that no data is available on how the VAS was assessed during treatment or on the time until pain relief was achieved. The tolerance of IONSYS 40 microgrammes was assessed on a total of 791 patients during controlled clinical trials. The most frequently reported adverse events were nausea, vomiting, headache and pruritis, generally of low to moderate intensity. Slight to moderate reactions at the application site were observed in fewer than 7% of patients treated with IONSYS. Erythema was observed in 53.8% of patients treated with IONSYS 24 hours after removal of the system. The studies took place over a too short period to allow assessment of the time taken for lesions to disappear and of whether there were any lasting effects on the skin. 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Moderate to severe post-operative pain causes a marked decline in post-operative quality of life. This medicine is a symptomatic treatment. It is a first-line treatment. Alternatives are available. Public health benefit: Moderate to severe post-operative pain in patients aged 18 to 75 represents a moderate public health burden according to its frequency. Improving control of post-operative pain is part of the public health requirement of improving the treatment of pain (cf. GTNDO: pain control 5 ). Considering the existing treatments, this proprietary product is expected to have an impact on morbidity and quality of life as it is much easier to use. It should in particular: - Make patients more comfortable as nursing care is simplified, - Improve patients' rehabilitation as they become mobilised earlier, - Reduce the risk of infection associated with perfusions and programming errors. In the absence of demonstration, it is difficult to quantify the expected impact. It can be regarded as minor. There is also likely to be an impact on medical care as the tasks of nurses are simplified. 5 Groupe Technique National de Définition des Objectifs [National Technical Objective Definition Group] (DGS-2003) 10

11 This proprietary product should go some way towards meeting the identified public health need. Therefore, the proprietary product IONSYS is likely to have a public health benefit. This interest is minor. The efficacy/adverse events ratio is high. The actual benefit is substantial Improvement in actual benefit IONSYS represents a minor improvement in actual benefit (IAB IV ) compared to patientcontrolled morphine perfusion. The improvement relates to simplification of post-operative pain control Therapeutic use 6,7,8 Post-operative pain must be regarded as an expected adverse effect of surgery. Analgesics that do not contain morphine (paracetamol and NSAIDs) are recommended for patients undergoing superficial surgery that does not cause significant pain, or if another technique is possible. NSAIDs are recommended following surgery with a high inflammatory factor (superficial, dental, ENT and orthopaedic surgery). Codeine is often used in combination with paracetamol to control moderate post-operative pain. There is no record of clinical assessment of dextropropoxyphene in post-operative pain control. Tramadol is suitable for PCA to control post-operative pain in patients for whom morphine is contra-indicated. Morphine remains the standard choice for post-operative analgesia in adults and children (IV administration titrated by low sequential doses with a subcutaneous relay or by IV in the form of patient-controlled analgesia). Fentanyl and pethidine are possible alternatives for post-operative pain control. Unlike morphine, plasma concentrations of fentanyl are similar for all administration routes, and the doses are identical at the same level of analgesia. IONSYS, a iontophoretic transdermal system in which the patient controls administration, is an alternative to morphine in the control of post-operative pain. The committee points out that this proprietary product should only be given to patients aged between 18 and 75 with a BMI of less than Société Française d Anesthésie et de Réanimation. Prise en charge de la douleur post-opératoire chez l adulte et l enfant : Conférence de consensus (1997) [French Association for Anaesthesia and Resuscitation. Control of post-operative pain in adults and children: Consensus-forming conference (1997) 7 Zetlaoui P.J. Conférence d actualisation : Titration morphinique. [Review conference: morphine titration] SFAR Société Française d Anesthésie et de Réanimation. Attitude pratique pour la prise en charge de la douleur postopératoire (1999). [French Association for Anaesthesia and Resuscitation. A practical approach to control of postoperative pain (1999). 11

12 4.4. Target population Around 8 million procedures involving administration of anaesthesia are performed in France each year. 70% of these are associated with surgery (i.e. 5.6 million procedures) and 20% of these surgical procedures are performed on children (i.e million procedures) 9. This means that around 4.5 million adult patients undergo surgery each year. Little epidemiological data is available on the prevalence of self-controlled analgesia. Around 20% of patients may have self-controlled analgesia after surgery 10,11. On this basis, the maximum population which could benefit from IONSYS is 900,000 patients Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services in the indication and at the dosage in the Marketing Authorisation. The Transparency Committee requests that one or more studies be organised to monitor patients treated with the proprietary product IONSYS in order to record, in an actual treatment scenario, the impact of the use of this system on pain control and the organisation of medical care. These studies should in particular describe: - The characteristics of patients receiving treatment (type of surgery, age, BMI, etc.) - The conditions of use (frequency and duration of treatment, other prescription drugs being taken, etc.) - The impact on pain levels (VAS score etc.) and the speed with which the patient experiences pain relief, - The impact on the simplification of treatment and its consequences for the patient and medical staff (satisfaction, comfort, use, time taken to receive fentanyl, speed with which the patient recovers mobility, etc.) - The frequency of any complications (overdose, infections, programming errors, local intolerance, etc.). The duration of the study, determined by an independent scientific committee, must be justified and sufficient to meet the committee requirements. The committee would also like to receive regular updates on the monitoring provided in the Risk Management Plan. 9 Clergue F, Auroy Y, Pequignot F, Jougla E, Lienhart A, Laxenaire MC. French survey of anesthesia in Anesthesiology Nov;91(5): Poisson-Salomon AS, De Chambine S, Lory C. Patient-related factors and professional practices associated with postoperative pain. Rev Epidemiol Sante Publique Sep;53 Spec No 1:1S opinions of specialists 12