Public Assessment Report Paediatric data. Durogesic Fentanyl Transdermal Patch 12,5; 25; 50; 75 and 100 mikrog /h

Transcription

1 Public Assessment Report Paediatric data Durogesic Fentanyl Transdermal Patch 12,5; 25; 50; 75 and 100 mikrog /h Marketing Autorisation Holder: Janssen-Cilag Oy Rapporteur: Co-Rapporteur: Paediatric assessment Procedure start date: Finland The Netherlands Date of this report:

2 2(25) I. INTRODUCTION I.1 Scope of the variation The scope of the variation is assess the paediatric data available for the product in the EU Work Sharing Project Assessment of Paediatric Data for Existing Products. The data provided is updated from the data submitted to the authorities of Germany and the Netherlands and FDA. It is stated by the MAH that no additional information to that already submitted to FDA and European Agencies that would impact the benefit-risk ratio of Durogesic for the paediatric population is available. The Expert reports were written by Dr. B. Zernikow, MD, from Witten/Herdecke University, Germany and by Prof. Dr Zuurmond, VU Medical Center, Amsterdam, The Netherlands. The process started on the 4 th October The following changes were originally proposed in the SPC by the MAH: 4.2 Posology and method of administration Pediatrics DUROGESIC should be administered only to opioid-tolerant pediatric patients (ages 2 to 16) who are already receiving at least 45 mg oral morphine equivalents per day. To convert pediatric patients from oral or parenteral opioids to DUROGESIC, refer to Equianalgesic potency conversion (Table 1), and Recommended DUROGESIC dose based upon daily oral morphine dose (Table 2). Table 2: Recommended DUROGESIC dose based upon daily oral morphine dose 1. Oral 24-hour Morphine (mg/day) For Pediatrics DUROGESIC Dose (mcg/h) For Pediatrics In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to DUROGESIC. 2 Conversion to DUROGESIC doses greater than 25 mcg/h is the same for adult and pediatric patients. 4.4 Special warnings and precautions for use Use in Children DUROGESIC should not be administered to opioid naïve pediatric patients (See Section 4.2 ) The potential for serious or life-threatening hypoventilation exists regardless of the dose of DUROGESIC transdermal system administered (See Tables 1 and 2 in Section 4.2 Posology and method of administration). DUROGESIC was not studied in children under 2 years of age. DUROGESIC should be administered only to opioid-tolerant children age 2 years or older (see Section 4.2, Posology and method of administration). To guard against accidental ingestion by children, use caution when choosing the application site for DUROGESIC (see Section 6.6, Instructions for use/handling) and monitor adhesion of the patch closely. 4.8 Undesirable effects

3 The adverse event profile in children and adolescents treated with DUROGESIC was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with DUROGESIC use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, vomiting, and nausea. 3(25) 5.2 Pharmacokinetic properties Adjusting for body weight, clearance in pediatric patients was about 20% higher than that in adults. These findings have been taken into consideration in determining the dosing recommendations for pediatric patients. 6.5 Instructions for use/handling In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch. II. II.3 SCIENTIFIC DISCUSSION Clinical aspects for Durogesic transdermal patch Fentanyl was first synthesised in Fentanyl interacts predominantly with the µ-opioid receptors. The pharmacological action of fentanyl is similar to that of morphine, primary therapeutic actions are analgesia and sedation. The analgesic potency of fentanyl is 75 to 100 times greater than morphine. Durogesic is a transdermal system providing continuous systemic delivery of fentanyl for up to 72 hours. The international birth date for Durogesic is March 1994, and since then there is an extensive experience in it s use in adults. Durogesic is approved in 64 countries and marketed in 57 countries. Through April 2004 the cumulative exposure of Durogesic transdermal patches was patches, corresponding patient days. There is an extensive experience with fentanyl in acute pain management is children. Fentanyl is commonly used for premedication and as adjunct to general anaesthesia for children above 2 years of age. During anaesthesia commonly provided initial dose range from 2 to 3 micrograms/kg intravenously; and supplements of 1 microgram/kg at 30 minutes intervals may be given. For pain relief after surgery fentanyl is used ad doses of 1 to 3 micrograms/kg by slow intravenous or intramuscular injection (Dsida RM, et al. Anesth Analg Jan;86(1):66-70). In paediatric pharmacotherapy fentanyl is also commonly provided as an adjunct to regional anaesthesia techniques, e.g. in epidural anaesthesia and pain management (Lejus C, et al. Br J Anaesth 1994; 72: 156-9, Lerman J, et al. Anesthesiology Nov;99(5): ). Oral and nasal transmucosal fentanyl is also used for sedation and analgesia before anaesthesia and painful procedures in children (Nelson PS, et al.. Anesthesiology 1989; 70: , Schechter NL, et al. Pediatrics 1995; 95: 335-9, Macaluso AD, et al. Anesth Analg 1996; 82: ). In adults Durogesic is registered for the management of chronic cancer pain and intractable pain requiring opioid analgesia, transdermal fentanyl is also used in the treatment of chronic non-cancer pain. In some countries including the USA, Germany and Netherlands, fentanyl patches have been approved also to be used in opioid-tolerant children aged 2 years and older. Durogesic transdermal patch is proposed to be used in the paediatric patients 2 years old or older for the same indication as those studied and approved in adults, i.e. for management of persistent, moderate to severe chronic pain that requires continuous, around-the-clock opioid administration for an extended period of time, and cannot be managed by other means. The process of diseases requiring

4 continuous opioid treatment for extended period of time is considered to be similar in adults and paediatric patients, and the outcome of therapy is likely to be comparable. Thus, the extrapolation from adult efficacy data is considered appropriate. Because of the risk for serious and life-threatening adverse effects of opioids, appropriate safety data in the target population is needed for this new administration route of fentanyl in children. 4(25) Durogesic contains a rate-limiting membrane that provides constant release of fentanyl, ensures continuous systemic delivery of the drug during the 72-hour application period. In adults upon initial Durogesic application, serum fentanyl concentrations increase gradually, reaching steady state at between 12 and 24 hours and remaining relatively constant for the rest of the application. In adults the serum fentanyl concentrations attained are proportional to the Durogesic patch size, and with repeated 72-hour applications, steady state serum concentration is maintained during subsequent applications of a patch of the same size. Fentanyl is metabolised in the liver by N-dealkylation and hydroxylation via CYP3A4. Fentanyl has no active or toxic metabolites. Metabolites and some unchanged drug are excreted mainly in the urine. The short duration of action of single dose of fentanyl is probably due to rapid redistribution into the tissues rather than metabolism and excretion. Following removal of the Durogesic transdermal patch, the serum concentrations of fentanyl slowly decrease with an average terminal half-life for adults of hours. Most pathways of fentanyl clearance are considered to be mature in children 2 years old and older. However, the bioavailability of different compounds from transdermal delivery systems in children has not been sufficiently described. Therefore, fentanyl pharmacokinetic from Durogesic transdermal patches, which is a new dosage form for systemic fentanyl administration in paediatric pharmacotherapy, should be described also in target population, because it is not known whether there are differences in skin characteristics between children and adults. Assessor s Conclusions: There is an extensive experience with fentanyl used in acute pain management in children and Durogesic transdermal patches in adults with chronic pain conditions. The pharmacokinetics of fentanyl as well as any other compounds from transdermal dosing systems is now well established, and there is only limited data on safety of extended period of fentanyl administration in children. Because fentanyl is associated with potential to life-threatening and serious adverse effects, that data is necessary for safe and efficient use of Durogesic in paediatric population. Clinical pharmacology Minimum effective analgesic serum concentrations of fentanyl in opioid-naive adults patients range from 0.3 to 1.5 ng/ml; adverse effects increase in frequency at serum levels above 2 ng/ml. Both the minimum effective concentration and the concentration at which toxicity occurs rise with increasing tolerance, but the rate of development of tolerance may vary widely among individuals. Fentanyl is metabolised primarily in the liver by CYP3A4 into inactive metabolites. Around 75% of fentanyl is excreted into the urine, mostly as metabolites, with less than 10% as unchanged drug. About 9% of the dose is recovered in the faeces, primarily as metabolites. In adults man values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.Fentanyl is a lipophilic compound, which makes it suitable for different administration routes including intravenous, intramuscular, epidural, spinal, transmucosal and also transdermal administration. DUROGESIC provides continuous systemic delivery of fentanyl at a relatively constant rate during the 72-hour application period. In adults after initial DUROGESIC application, serum fentanyl concentrations increase gradually, generally leveling off between 12 and 24 hours and remaining relatively constant for the remainder of the 72-hour application period. After DUROGESIC is removed, serum fentanyl concentrations decline gradually, falling about 50% in about 17 (range 13-

5 22) hours. Continued absorption of fentanyl from the skin accounts for a slow disappearance of the drug from the serum. Method 5(25) To characterize pharmacokinetics of fentanyl form DUROGESIC in children a population PK model was applied on pooled data from two studies.. During follow-up visits at days 1, 2, 4, 5, 7, 10, 13 or 16 altogether 5 samples for each child were obtained. A linear mixed-effects modelling was applied for population PK calculations. The 242 children provided 886 evaluable serum samples, 188 samples from 50 subjects in FEN-INT- 24 and 698 samples form 192 children in FEN-UUSA-87. Serum samples were analysed using an immunoassay method (LLQ 0.1 ng/ml). The following covariates were tested; time from dosing, study centre, site, age, weight, height, BSA, BMI,LBM, gender, race, body temperature, system location, sexual maturity, dosing gap, and concomitant use of CYP3A4 inducers or inhibitors. PK-PD relationships between incidence of AE and fentanyl serum levels were investigated as well. Results PK The serum fentanyl concentrations were twice as high in children compared to those in adults at similar doses. This could be explained by a lower clearance (Cl) in children, 28±15 L/h than that observed in adults, 48±19 L/h. However, body weight adjusted Cl was 20% higher in children, 0.9±0.5 L/h, than that observed in adults, 0.8±0.3 L/h. BSA adjusted Cl was 26±13 L/h/m 2 in children, and 19±7 L/h/m 2 in adults. Study site affected the fentanyl concentrations but there were no other significant relationship between Cl and any other co-variate in the study population. The study design and the data obtained did not allow a calculation of the volume of distribution. PK-PD No significant relationships between the incidence of adverse events, e.g. fever, vomiting, nausea, anemia, abdominal pain, and fentanyl serum concentrations could be identified. The relationship between clearance and BSA is given in the graph below. Assessor s comments: In children, fentanyl exposure from DUROGESIC was significantly higher than that observed in adults. This should be taken in account while comparing conversion tables from

6 6(25) morphine equivalents to Durogesic dosing in children. However, opioids treatment should be titrated individually for each patient, as the pain level and opioids-tolerance varies significantly from patient to patient. Based on PK parameters lower initial doses of DUROGESIC should be used in children compared to that used in adults. Moreover, in dose titration the dosing of DUROGESIC should be slow while treating children with low body weights. In addition, the effects of different application site on PK of fentanyl from DUROGESIC in children should be discussed, because it is proposed that in young children, the upper back is the preferred location to apply DUROGESIC to minimize the potential of the child removing the patch. Applicant s response: In adults the serum fentanyl profile and the total exposure ( AUC values ) were similar when applied to the upper outer arm ( Mean ± SD AUC : 219 ± 69 ) and the upper back ( Mean ± SD AUC : 209 ± 63 )and was about 20 % to 25 % lower when applied to the chest ( Mean ± SD AUC: 165 ± 36 ). However, in general the range of Cmax and AUC values seen for upper chest was within the range seen for the upper arm and upper back (see Figure 1 ). In the paediatric population "patch application site " was tested as a covariate and was not found to have significant effect on the pharmacokinetics of fentanyl. The application site included chest, back, flank and upper arm with preference given to the back. Thus, fentanyl pharmacokinetics following application to upper back is expected to be similar to the other sites based on both the adult and paediatric data. Since upper back was also the preferred site in the safety study, it is the recommended site in the paediatric population. Table 1 above, summarizes fentanyl clearance by age group and Figures 2 and 3 show CL / F ( L / hr ) as a function of age and weight, respectively. Figure 4 shows CL / F ( L / hr / Kg ) adjusted to body weight as a function of age. As seen in these Figures, CL / F increases as a function of age and body weight but CL / F adjusted to body weight decreases with increasing age. This is consistent with morphine kinetics in paediatric patients (Dampier et al, 1995 ; Hunt et al, 1999, see Appendix 4 ). Hunt et al studied morphine kinetics in children with cancer receiving morphine as immediate release morphine liquid or sustained release tablets. Forty children with a median age of 11.4 years (range 1.7

7 7(25) to 18.7 years), received a median dose of 1.4 mg / Kg / d ( range 0.4 to 24.6 mg / Kg / d ). Plasma clearance of morphine was 23.1 ml / minute per Kg body weight and children under 11 years had significantly higher clearance and larger volume of distribution for morphine and its glucuronides than older children and adults. Similar observation was made by Dampier et al who reported that there was negative correlation between clearance and age over the age range studied ( 6 to 19 years ) in 24 sickle cell patients receiving intravenous morphine. Since pharmacokinetics (CL / Kg ) of both fentanyl and morphine as a function of age behave similarly (decrease in CL / Kg with increase in age ), it is reasonable to base the dose of Durogesic in the paediatric patient on stable dose of morphine. The paediatric patients enrolled were on stable morphine doses that were well tolerated. Clinical efficacy Main studies The efficacy of Durogesic fentanyl transdermal patches has been evaluated in three phase 3 studies in paediatric patients requiring continuous opioid analgesia.the intent-to-treat children population consisted 293 children with 235 children with data for day 16 (considered as completers). Methods Study 1: A 15-Day Trial to Document the Safety, Clinical Utility and Pharmacokinetics of Duragesic (TTS Fantanyl) in the Treatment of Pediatric Subjects with Continuous Pain Requiring Opioid Therapy. The objective was to determine the safety, clinical utility, and pharmacokinetics of 12.5 microg/h Duragesic in the treatment of paediatric subjects aged 2-12 years with continuous pain requiring the use of a potent opioid.the trial design was single-arm, non-randomised, open-label, multicentre trial with a 15-day primary treatment period followed by a long-term treatment extension period of up to 1 year. Patients were included if they were between 2-12 years of age, suffered from continuous pain of well documented etiology and had a pain that required treatment with an opioid.patients were excluded if they had a history of allergy or hypersensitivity to fentanyl or morphine, active skin disease that precluded application of Duragesic of which may have affected the absorption of fentanyl or local tolerability and those with life expectancy that was less than 1 months. The initial dose of Duragesic was 12.5 microg/h (1 patch). The patches were to be replaced every 72 hours. An increased does may have been used when higher dose was needed based on rescue medication consumption and pain assessment. Demographic data and baseline characteristics were summarised descriptively, and safety, efficacy and clinical utility data were summarised for the intent-to-treat population Results A total of 53 subjects (28 boys/25 girls) in 13 study centres in Europe were enrolled and included in the intent-to-treat population. 29 subjects were 2-6-years old, and years old, a mean age was 6,5±0,5 years. Fourtyfive out of 53 subjects had prior opioid exposure; 29 morphine, 9 tramadol. Safety Eleven subjects were withdrawn due to death (10 died during the trial and 1 after withdrawal), 4 subjects due to insufficient response, 3 due to adverse events, 3 subjects were ineligible to continue the trial, 1 withdraw the consent.

8 8(25) One or more adverse events were developed in 45/53 subjects. The most common adverse events were fever (18), anaemia (15), nausea (13), vomiting (11), thrombocytopenia (11), constipation (9), pain (8), pruritus (8), progression of neuroblastoma (6) and somnolence (6). Ten patients died during the study and 1 after withdrawing from the study (leukaemia). None of the deaths were considered by the investigator to be related to treatment with Durogesic. One or more serious adverse events were developed in 19/53 subjects. Two subjects had serious adverse events that were considered by the investigator to be related to treatment with Durogesic (hyperaesthesia and pain; stupor, miosis, somnolence, and respiratory disorder). Three treatments were stopped due to adverse events. The treatment was stopped in one with hyperaesthesia and pain of hands and feet (a serious event), in one with fatigue, speech disorder, and abnormal thinking, and in one with constipation. All these were considered by the investigator to be related to treatment with Durogesic. Three children required dose reduction due to an adverse event. The data is provided in the Table 1 below. Table 1. Safety data in Study 1 Pharmacokinetics The average daily Durogesic dose was 16.9±1.3 microg/h. Most of the subjects (68%) never required an upward titration of Durogesic above the initial dose during the primary treatment period. The serum concentration reached steady state at 24 hours post first application. No apparent accumulation of fentanyl occurred during 5 patch treatment over 15 days. Dose proportionality was observed for fentanyl from 12.5 to 37.5 microg/h. Efficacy Clinical utility but not efficacy was one of the main objectives of the study. The clinical utility was assessed by treatment assessment, global assessment, pain levels, rescue medication, and play performance. In the treatment assessment patients/parent used a 4-point scale from poor to very good, global assessment was the investigator and parents completed a 4-point scale from poor to excellent. Pain level was measured using the Bieri Faces Scale and the Varni-Thompson VAS. For subjects who had a treatment assessment of fair or poor regarding their current pain therapy at baseline, the majority (18/28) improved to an assessment of good or very good with Durogesic at

9 endpoint. For subjects who had a treatment assessment of good or very good at baseline, the majority (13/14) remained so at the endpoint. 9(25) Average daily pain intensity levels assessed by the subjects decreased steadily over time, and overall, an improvement in the subject s functioning based on the Final Play Performance Scale score was also observed. Applicant s Conclusions It was concluded that Durogesic appeared to be safe and well tolerated in children with continuous pain requiring opioid therapy. Serum fentanyl concentration showed intersubject variability and does proportionality for the 12.5 to 37.5 microg/h dosages. Methods Study 2: A study to Assess the Safety, Dose Conversion, and Titration of Durogesic (fentanyl trandermal system) in Pediatric Subjects with Chronic Pain Requiring Opioid Therapy The objective was to determine the safety of treatment initiation and titration with Durogesic with 12.5 to 100 microg/h in paediatric subjects requiring opioids therapy. A secondary objective was to determine population pharmacokinetics of Durogesic in paediatric patients. The study design was single-arm, non-randomised, open-label, multicentre trial with a 15-day primary treatment period followed by a continued therapy until Durogesic is approved for the use in children. Patients were included if they were between 2-16 years of age, suffered from continuous pain of well documented etiology and had a pain that required continuous treatment with an opioid. Received opioids continuously for a minimum of 7 days prior the enrolment with a projected need for continuous opioids for at least the length of the primary treatment period (15 days), received the equivalent of at least 30 mg of oral morphine the day prior to enrolment based on the dose conversion. Patients were excluded if they had a history of allergy or hypersensitivity to fentanyl or other opioids or adhesives; active skin disease that precluded application of Durogesic of which may have affected the absorption of fentanyl or local tolerability; subjects with pain due to surgery and those with life expectancy that was less than 15 days. The initial dose of Durogesic was based on a determination of opioid analgesic requirement during the previous 24-hours period. The dose was then determined by using an Equianalgesic Potency Conversion Table. Following initiation the subjects were titrated every 3 days until the pain was subjectively controlled/improved. Demographic data and baseline characteristics were summarised descriptively, and safety, efficacy and clinical utility data were summarised for the intent-to-treat population Results A total of 199 subjects (118 boys/81 girls) in 66 study centres internationally were enrolled and included in the intent-to-treat population. 109 were Caucasian, 43 hispanic, and 40 were black. 27 subjects were 2-5-years old, 67 were 6-11 years old, and 102 were years old, a mean age was 10,7±0,3 years. All subjects had prior opioid exposure, most commonly morphine, in 140/199 children. The demographic and baseline characteristics of the patients are given in the Table 4-4 below.

10 The previous opioid medication taken by at least 5 % of subjects is presented in Table (25)

11 11(25) Thirty subjects (65%) completed the primary treatment period. 26 subjects (13%) were withdrawn during the primary treatment period, 6 due to death (3%), 3 subjects due to insufficient response, 3 subjects were ineligible to continue the trial, 3 withdraw the consent, and 2 due to incompliance, 1 due to Durogesic no longer needed, 1 decreased pain and 1 subject likely discharged. Of the 130 subjects who entered the extension treatment period, 104 (80%) discontinued the treatment with Durogesic. 21 subjects (16%) discontinued due to death, 13 subjects (10%) were ineligible to continue the trial, 11 subjects (9%) due to adverse events, 7 subjects (5%) due to insufficient response, 9 (7%) withdraw the consent, and 1 due to incompliance. 22 subjects were weaned off of opioids, in 2 pain increased, 2 subjects required increased patch changes. Safety One hundred and eighty subjects out of 199 (91%) developed 1 or more adverse events. The incidence of adverse events was higher during the primary treatment period (87%) compared with the extension treatment period (66%). The most common adverse events were fever (36%), vomiting (33%), nausea (21%), headache (19%), abdominal pain (17%), diarrhoea (14%), anaemia (13%), pruritus (12%), and constipation (12%). Half of the children had adverse events that were considered by the investigator to be related to trial medication, vomiting 16%, nausea 11%, pruritus 8%, application site reaction 8%, headache 7%, constipation 6% and somnolence 6%. Fifty-three children (27%) died during the primary and extension treatment period. One of the 53 deaths was considered by the investigator to be doubtfully related to treatment with Durogesic. 86/199 subjects (43%) developed 1 or more serious adverse events. 19 subjects (10%) had serious adverse events that were considered by the investigator to be related to treatment with Durogesic (most common vomiting in 3% and pain in 2%). 19 treatments (10%) were stopped due to adverse events, 7 during the primary treatment period and 12 during the extension treatment period. Nausea, vomiting, stupor, and fever, each reported in 2 children, were the most common adverse events leading to withdrawal from the study. 14/19 children who discontinued the treatment due to adverse events were aged years. Eighteen children required dose adjustment due to adverse events, 11 subjects has increases, 6 decreases and 1 both. The safety results are given in the Table below.

12 12(25) Pharmacokinetics The mean average daily Durogesic dose was 1.1±0.06 microg/kg/h. Subjects 2-5 years of age had the highest per-kilogram dose requirements. Most of the subjects (61%) never required an upward titration of Durogesic above the initial dose during the primary treatment period. A large variability in concentration was observed between subjects, as evidenced by CV generally greater than 50% at all dose levels. However, serum concentrations were comparable on average across time intervals following application of the first patch as well as subsequent patches. Efficacy Although not specified as a study objective, evaluation of effectiveness/clinical utility was performed in the study. The clinical utility was assessed by global assessment of pain treatment, pain intensity levels, play performance score and titration information. For subjects who had a treatment assessment of fair or poor regarding their current pain therapy at baseline, the majority (79%) improved to an assessment of good or very good with Durogesic at endpoint. For subjects who had a treatment assessment of good or very good at baseline, the majority (95%) remained so at the endpoint. Average daily pain intensity levels assessed by the subjects decreased steadily over time, and overall, an improvement in the subject s functioning based on the Final Play Performance Scale score was also observed. Applicant s Conclusions It was concluded that there were no adverse events associated with Duragesic that indicated a paediatric-specific risk. The observed adverse events were considered to be consistent with that of a potent opioids in a population with serious medical condition. Serum fentanyl concentrations showed considerable intersubject variability. Exposure to fentanyl generally increased with dose, but substantial overlap existed across doses, as previously seen in adult subjects. Methods

13 13(25) Study 3: A study to assess safety, efficacy and pharmacokinetics of Durogesic in the treatment of paediatric subjects with chronic pain requiring long term opioid therapy. The objective was to determine the safety, efficacy, and pharmacokinetics of Durogesic in the treatment of paediatric subjects aged 2-18 years with continuous pain requiring the use of a morphine 30 mg or more. The trial design was single-arm, non-randomised, open-label, multicentre trial with a 15-day primary treatment period followed by a long-term follow-up period of up to 6 months. Patients were included if they were between 2-12 years of age, suffered from continuous pain of well documented etiology, malignancy or other life-threatening terminal disease and had a pain that required treatment with an opioid. Patients were excluded if they had a history of allergy or hypersensitivity to fentanyl or morphine, active skin disease that precluded application of Durogesic of which may have affected the absorption of fentanyl or local tolerability. The children were switched from morphine to Durogesic following the guidelines for dose conversion. For statistical comparisons binominal test and non-parametric sign test were used. Results A total of 41 subjects (30 boys/11 girls) in 11 study centres were enrolled and included in the intentto-treat population. A median age was 10.5 [ ] years. Twenty-six out of 41 children completed the treatment phase. 15 subjects were withdrawn during the 15-days treatment phase During the 15-days treatment phase 8 subjects were withdrawn due to adverse events, 4 due to insufficient response (2 died within 2-3 days), and 3 subjects withdrew the consent. Four out of 23 subjects completed the 12 weeks follow-up phase. 19 subjects were withdrawn during the follow-up phase. During the follow-up phase 9 subjects were withdrawn due to adverse events, 2 due to insufficient response, 2 because the patient became asymptomatic/cured, 3 subjects withdrew the consent, and 3 were lost for follow-up. The initial dose of was 25 microg/h in 33 subjects, and 50 microg/h in 6 children. The patches were to be replaced every 72 hours. An increased does may have been used when higher dose was needed based on rescue medication consumption and pain assessment. The starting doses and dose changes are given in the Display below.

14 14(25) Efficacy The primary efficacy parameter was the patient global treatment assessment by patients/parent on a 4- point scale from poor to very good. Twenty-seven out of 36 (75%) of subjects were assessed the patch good/very good. The data is given below.

15 15(25) Safety 25/41 children died during the treatment and follow-up period. None of the deaths was considered by the investigator to be related to treatment with Duragesic. 32/41 subjects developed 138 adverse events during the 15-days treatment phase, 14 developed 36 serious events. During the follow-up phase 6/23 subjects developed 104 adverse events, 13 developed 38 serious events. 65/242 adverse event were considered possibly/definitely related to the trail medication. The most common adverse events were vomiting (22), agitation (18), fever (14), nausea (13), pain (6), and pruritus (4), progression of neuroblastoma (6) and somnolence (6). Twenty-eight out of 41 subjects developed 1 or more serious adverse events. 3 subjects had 5 serious adverse events that were considered by the investigator to be possibly related to treatment with Durogesic (constipation; cerebral seizure; and apnoea, heart disorder and myopathy). No severe skin sites reactions were reported. At day 15 assessment 7/26 children had mild-moderate erythema, 1 had itching, 5 oedema and 1 papules/pustules at the application site. Pharmacokinetics Only few blood samples were obtained for determination of pharmacokinetics and blood samples were collected only from 9 children, and thus no formal pharmacokinetic analysis could be performed. A large variability in concentration was observed between subjects, however, serum concentrations were comparable on average across different dose levels, mean 1-2 ng/ml at steady state. Applicant s Conclusions It was concluded that Durogesic was efficacious and well tolerated, and that the adverse effects did not from that of other opioids analgesics.

16 16(25) Analysis performed across trials In the global assessment of these three studies the applicant summaries that effectiveness and clinical utility parameters supports using Durogesic in patients aged 2 years or older with chronic pain requiring the use of an opioid analgesic. The evidence of effectiveness of Durogesic is summarised as: Average daily pain intensity levels assessed by the patients or parents decreased steadily over time on all pain scales employed Approximately 85% of patients took at least one rescue medication during the primary treatment period, but Durogesic provided over 90% of total daily opioid dose. Overall, patients functioning improved based on the final Play Performance Scale scores. Improvements were associated with reduction of pain intensity as assessed by the patients and investigators, and with the patients positive assessment of treatment in terms of convenience, pain control, and side effects. More than two-thirds of parent and investigator global assessment of pain treatment (pain control) at endpoint were excellent or good. Applicant concludes that based upon the various effectiveness measures examined in the course of this clinical program, it is apparent that Durogesic provided effective analgesia in children and adolescents requiring chronic opioid treatment. Assessor s Conclusions on Clinical Efficacy: The clinical studies in this programme were conducted according to the key requirements for Good Clinical Practice (GCP), as documented by the International Conference on Harmonisation (ICH). Various methods were used for outcome assessment. For pain level assessment a coloured vertical Visual Analogue Pain Scale (VAS) and Numeric Pain Intensity Scale (NPI) the Bieri Faces Scale and the Varni-Thompson Visual Analogue Scale, and the McGrath Faces Scale in were used in the studies.. This makes the comparison of pain levels across the trials difficult. However, all scales are validated and commonly used in paediatric pain studies, and could therefore be considered as appropriate tolls for measurement of pain intensity.use of rescue pain medication was used as a surrogate measure of adequacy of analgesic efficacy, and this is considered as an appropriate. Play Performance Status score (PPS) is also considered as an appropriate method to evaluate the changes in function and activity during the course of Durogesic treatment. The sample size of 293 children is considered sufficient to provide efficacy data in the target population. The gender (176 boys) and age distribution, (2-6-years old: 66 patients, 6-12years old: 100 patients, and years old: 117) is also considered to provide sufficient data across different ages. In general the main outcomes were similar regardless of patients age or sex. Thus it is considered that sufficient efficacy data has been provided for the target population: for children age 2 years or older requiring opioid treatment for persistent moderate to severe pain who are already on opioid treatment and who have demonstrated opioid tolerance. Clinical safety The applicant has reviewed Durogesic s adverse events and suspected adverse reactions in children aged less than 18 years. The applicant could identify 114 spontaneous reported cases and 250 clinicaltrial cases Patient exposure

17 Patient exposure in children aged less than 18 years is not available. Through April 2004 the cumulative exposure of transdermal patches was patches, corresponding patient days. 17(25) Adverse events There were 114 spontaneous reported cases and 250 clinical-trial cases. Seventy-six out of 114 of the spontaneous cases were reported in children years of age, 18 cases in children 6-11 years, and 20 cases in younger children. Fifty-six out of 114 spontaneous reported cases were medically confirmed. Most common adverse events were application sites reactions (9), medication error (7) and somnolence (6). The cumulative medically confirmed spontaneous reports in patients less than 18 years of age are given in the tables below.

18 18(25)

19 19(25) One hundred and ten out of 250 (44%) of the clinical-trial cases were reported in children years of age, 93 cases (37%) in children 6-11 years, and 47 cases (19%) in younger children. Most common adverse events in the clinical-trial cases were malignant neoplasm aggravated (50), condition aggravated (48), pyrexia (43), and vomiting (25). The Table below provides the information on cumulative clinical trial reports of adverse drug events. Serious adverse events and deaths There were 19 spontaneous reported cases and 106 clinical-trial cases with fatal outcome. Fourteen out of 19 of the spontaneous reported cases with fatal outcome were medically confirmed. Fourteen out of 19 of the spontaneous cases were reported in children years of age, 3 cases in children 6-11 years, and 2 cases in younger children. Seven cases had either an adverse event, indication of drug abuse or intentional misuse; 5 cases of use for acute pain postoperative pain; 2 case for mononucleosis; 3 cases due to progression of the underlying malignancy; and 2 cases of inappropriate exposure, and in 8 cases for acute pain indications. There were 106 clinical-trial cases with fatal outcome, most common adverse events were progression of the underlying malignancy (50), condition aggravated (38), and respiratory failure (10). Applicant s Conclusions It was concluded that the adverse events from clinical trials and adverse experiences form postmarketing safety data in paediatric population affirms the type and characteristics of events

20 currently noted for Durogesic. The safety profile is consistent with what would be expected for a narcotic analgesic and it includes somnolence, nausea, CNS and respiratory depression and its sequelae, drug abuse, and application site reactions due to topical formulation. A true estimate of paediatric exposure for Durogesic is not available. 20(25) Assessor s Conclusions on Clinical Safety: With regards to the reported adverse events for Durogesic transdermal patches in clinical trials and spontaneous reported cases should considered in the context of the underlying conditions. The safety of Durogesic has been evaluated in 293 children in clinical trials. The adverse event profile was similar to that observed in adults, and the data indicates that there may not be any increased paediatric-specific risk beyond that expected with the used of opioids for the relief of pain associated with serious underlying illness. The most common events were malignant neoplasm aggravated and condition aggravated. In spontaneous reports several cases reported the use of Durogesic for acute pain conditions (= offlabel) or drug abuse/misuse and overdoses, some of which were clearly intentional. In addition fatalities have occurred with accidental topical exposures and with acute ingestion. The warnings of not to used Durogesic for acute pain management and that patches should be kept out of reach of children are appropriate in the SPC and PIL. The MAH is investigating the effect of patch taping on the transdermal drug delivery and efficacy. This data should be provided for assessment as soon as it is available as a post-approval commitment. The MAH will submit the PSURs annually. The MAH also agrees to summarise the cases for special populations, including paediatrics, in future PSURs. The MAH agrees to monitor cases of drug administration error and medication error and summarise the cases in future PSURs. III. OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT The clinical studies in this programme were conducted according to the key requirements for Good Clinical Practice (GCP), as documented by the International Conference on Harmonisation (ICH). Various methods were used for outcome assessment. For pain level assessment different scales were used. This makes the comparison of pain levels across the trials difficult. However, all scales are validated and commonly used in paediatric pain studies, and could therefore be considered as appropriate tolls for measurement of pain intensity. The use of rescue pain medication was used as a surrogate measure of adequacy of analgesic efficacy, and this is considered as an appropriate. The sample size of 293 children is considered sufficient to provide efficacy and safety data in the target population. In general the main outcomes were similar regardless of patients age or sex. Thus it is considered that sufficient efficacy data has been provided for the target population: for children age 2 years or older requiring opioid treatment for persistent moderate to severe pain who are already on opioid treatment and who have demonstrated opioid tolerance. Regarding the reported adverse events for Durogesic transdermal patches in clinical trials and spontaneous reported cases should considered in the context of the underlying conditions. The adverse event profile was similar to that observed in adults, and the data indicates that there may not be any increased paediatric-specific risk beyond that expected with the used of opioids for the relief of pain associated with serious underlying illness. The most common events were malignant neoplasm aggravated and condition aggravated. Overall, the risk/benefit assessment of the use Durogesic transdermal patch for the proposed indication in paediatric patients over 2 years of age is considered positive. The Applicant has provided

21 21(25) satisfactory responses to the comments raised by the MSs. The Applicant is investigating the effect of patch taping on the transdermal drug delivery and efficacy of the fentanyl in paediatric patients. This data should be provided for assessment as soon as it is available as a post-approval commitment. The Applicant will also submit the PSURs annually for the first three years, and follow the adverse effects and medication errors of Durogesic in the future PSURs. The agreed sections of the SPC in this procedure are presented in Annex 1 below. The MAH has been requested to submit an application for a type II variation in order to implement SPC changes nationally.

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