Public Assessment Report for paediatric studies submitted in accordance with Article 46 of Regulation (EC) No1901/2006, as amended.

Transcription

1 Public Assessment Report for paediatric studies submitted in accordance with Article 46 of Regulation (EC) No1901/2006, as amended Atomoxetine Strattera UK/W/010/pdWS/005 Rapporteur: UK Finalisation procedure (day 120): 12 February 2014 Date of finalisation of PAR 13 March 2014 UK/W/010/pdWS/005 Page 1/37

2 ADMINISTRATIVE INFORMATION Invented name of the medicinal product(s): INN (or common name) of the active substance(s): MAH (s): Currently approved Indication(s) Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): See section VII Atomoxetine See section VII Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children of 6 years and older, in adolescents and in adults as part of a comprehensive treatment programme. Treatment must be initiated by a specialist in the treatment of ADHD, such as a paediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis should be made according to current DSM criteria or the guidelines in ICD N06BA09 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg and 100mg capsules UK/W/010/pdWS/005 Page 2/37

3 CONTENTS I. EXECUTIVE SUMMARY... 4 II. RECOMMENDATION... 5 III. INTRODUCTION... 6 IV. SCIENTIFIC DISCUSSION... 6 IV.1 INFORMATION ON THE PHARMACEUTICAL FORMULATION USED IN THE CLINICAL STUDY(IES)... 6 IV.2 NON CLINICAL ASPECTS... 6 IV.3 CLINICAL ASPECTS... 6 IV.4 INTRODUCTION... 6 IV.5 CLINICAL STUDIES... 7 IV.6 PHARMACOKINETIC, EFFICACY, AND SAFETY EXTRAPOLATION ANALYSES PHARMAKOKINETIC EXTRAPOLATION COMPARATIVE DATA FOR EFFICACY AND SAFETY V. DISCUSSION ON CLINICAL ASPECTS AND CONCLUSION... Error! Bookmark not defined. VI. MEMBER STATES OVERALL CONCLUSION AND RECOMMENDATION VII. LIST OF MEDICINAL PRODUCTS AND MARKETING AUTHORISATION HOLDERS INVOLVED UK/W/010/pdWS/005 Page 3/37

4 I. EXECUTIVE SUMMARY This is a submission of data for atomoxetine in accordance with Article 46 of the Regulation (EC)No 1901/2006, as amended, on medicinal products for paediatric use. Atomoxetine (Strattera 10mg, 18mg, 25mg, 40mg, 60mg, 80mg or 100mg hard capsules) is licensed in the EU for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children of 6 years and older and in adults as part of a comprehensive treatment programme. Treatment must be initiated by a specialist in the treatment of ADHD, such as a paediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis should be made according to current DSM criteria or the guidelines in ICD. The SmPC states in section 4.2 that the safety and efficacy in children under 6 years of age have not been established. Therefore, the drug should not be used in children under 6 years of age. The SmPC contains a suicidality warning in section 4.4 Special warnings and precautions for use. (see below). The MAH stated that the submitted paediatric data do not require consequential regulatory action. No changes to the product information are proposed. Two reports were submitted: a clinical trial report synopsis for the prematurely stopped trial B4Z- XM-O024 (report dated 14 February 2013), and a report on the PK, efficacy and safety extrapolation analysis for the EU Paediatric Investigation Plan (report dated 29 June 2012). No completed paediatric clinical trials were submitted for assessment. The prematurely terminated trial was an open-label study exploring the effect of a structured psychoeducational program on medication adherence in pharmacologically naïve children with ADHD aged 6-12 years, versus no psychoeducational program. Subjects were permitted to receive any standard pharmacological ADHD therapy. At 12 months, 13.2% patients in the intervention group and 14.3% patients in the control group had discontinued pharmacological treatment (primary endpoint) indicating that the psychoeducational program did not result in superior adherence to medication. A review of the provided treatment emergent adverse events by SOC and preferred term did not raise any new safety concerns. The results from this open-label prematurely terminated trial do not merit reflection in the product information. The data submitted under the title of Pharmacokinetic, Efficacy, and Safety Extrapolation Analyses provide the following information: PK modelling data showed the predicted pharmacokinetic profiles of 0.5mg/kg and 1.2 mg/kg doses in 4 to 5 year olds are similar to that of children at least 6 years of age. Observed atomoxetine plasma concentration in a subset of patients with body weights comparable to that expected for 4 year olds ( 21.9 kg) and 5 year olds (21.9 to 25.1 kg) were similar to the rest of patients in the database with body weights >25.1 kg. Inclusion of PK data for children aged less than 6 years in the product information is not considered justified as data on long-term efficacy and/or safety are not available. A comparison of efficacy data across four analysis groups demonstrated that acute atomoxetine treatment was effective in improving core ADHD symptoms in both the 6 to 7 year olds and 5 year olds. The treatment effect, as measured by the mean change from UK/W/010/pdWS/005 Page 4/37

5 baseline ADHDRS-IV-Parent:Inv total score, was smaller in the 5 year olds ( -7.42) than in the 6 to 7 year olds ( ). Inclusion of efficacy data for children under the age of 6 year in the product information is not considered justified because short-term randomised placebo controlled data are limited to 19 subjects, and there are no data on long-term efficacy and/or safety in this age group. An analysis of adverse event data across age groups (6 to 7 year olds versus 4 to 5 year olds) indicated an increased incidence of decreased appetite, irritability, fatigue, sedation and mood-related adverse in children under the age of six years. Decreases in weight were observed in the younger age group whilst increases in weight were observed in the older age group, but treatment duration for younger children was considerably shorter than for older ones (64 days versus 352 days). No atomoxetine-treated patient 5 years of age met the criteria for increased systolic or diastolic blood pressure and changes in pulse appeared to be less pronounced in the 4 to 5 year olds, but the sample size for younger children was small and treatment duration was short. Additional subgroup analyses for safety parameters by gender, ADHD subtype and prior stimulant use were provided with the responses to the Request for Supplementary Information (RSI). These indicated that gastrointestinal disorders were slightly more common in patients without compared to patients with previous stimulant use; psychiatric disorders were somewhat more common in patients with previous stimulant use. Inclusion of safety data for children under the age of 6 year in the product information is not considered justified, because atomoxetine is not indicated in children younger than 6 years and available safety data are derived from a small sample of children who were exposed for a short duration of time. II. RECOMMENDATION The provided efficacy and safety data for children aged less than 6 years are derived from a small sample size and do not merit reflection in the product information. Long-term safety data are not available for this age group. The product information currently states in section 4.2 that The safety and efficacy in children under 6 years of age have not been established. Therefore, the drug should not be used in children under 6 years of age. This statement adequately reflects the available data. No changes to the product information are required as a result of this procedure. UK/W/010/pdWS/005 Page 5/37

6 III. INTRODUCTION Atomoxetine (Strattera 10mg, 18mg, 25mg, 40mg, 60mg, 80mg or 100mg hard capsules) is licensed in the EU for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children of 6 years and older, in adolescents and in adults as part of a comprehensive treatment programme. Treatment must be initiated by a specialist in the treatment of ADHD, such as a paediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis should be made according to current DSM criteria or the guidelines in ICD. The SmPC states in section 4.2 that the safety and efficacy in children under 6 years of age have not been established. Therefore, the drug should not be used in children under 6 years of age. The SmPC contains a suicidality warning in section 4.4 Special warnings and precautions for use. The MAH (Eli Lilly) submitted the following data for atomoxetine, in accordance with Article 46 of the Regulation (EC) No 1901/2006, as amended, on medicinal products for paediatric use. A clinical study report synopsis for the prematurely stopped trial B4Z-XM-O024 (report dated 14 February 2013) plus a Clinical Overview for this trial A report on the PK, efficacy and safety extrapolation analysis for the EU Paediatric Investigation Plan (report dated 29 June 2012). An Extrapolation Report Addendum (report dated 24 October 2013) containing additional subgroup analyses for safety parameters by gender, ADHD subtype and prior stimulant use were provided with the responses to the RSI. No paediatric studies were completed by the applicant. No Periodic Safety Update Report (PSUR) was provided. No new published data have been provided. The MAH stated that the submitted paediatric data do not require consequential regulatory action. No changes to the product information are proposed. IV. IV.1 SCIENTIFIC DISCUSSION Information on the pharmaceutical formulation used in the clinical study(ies) Not applicable. IV.2 Non-clinical aspects Not applicable. IV.3 IV.4 Clinical aspects Introduction Two reports were submitted: a synopsis clinical trial report for the prematurely stopped trial B4Z- XM-O024 (report dated 14 February 2013), and a report on the PK, efficacy and safety extrapolation analysis for the EU Paediatric Investigation Plan (report dated 29 June 2012). UK/W/010/pdWS/005 Page 6/37

7 IV.5 Clinical studies The MAH submitted the synopsis report of one prematurely terminated study. Study Title: B4Z-XM-O024 Clinical Study Report Synopsis Study for Evaluation of a Parent-Psychoeducational Program in the Adherence of Treatment in Children with Attention Deficit/Hyperactivity Disorder (ADHD) in Pharmacological Treatment Study Design The study was a 12-month cluster randomized, open, prospective study with two parallel groups consisting of an: Intervention group: patients with a new diagnosis of ADHD who were to begin pharmacological treatment who were included in a psychoeducational program Control group: patients with a new diagnosis of ADHD who were to begin pharmacological treatment but were not included in any psychoeducational program. The psychoeducational program comprising 4 weekly sessions, followed by a 5th session five weeks after session 4. All patients received standard therapy for ADHD determined by the investigator and according to the international guidelines provided by the National Institute for Health and Clinical Excellence (NICE), including atomoxetine. Objectives Primary objective To prospectively explore the impact on Attention Deficit/Hyperactivity Disorder (ADHD) medication adherence in terms of time until withdrawal of pharmacological treatment of a structured psychoeducational program compared to not receiving the psychoeducational program in parents of patients with a new diagnosis of ADHD who started pharmacological treatment following the current international guidelines. Treatment withdrawal was defined as the discontinuation of treatment for any cause. The primary outcome measure was the time to withdrawal of pharmacological treatment, defined as the time from the date of randomization to the date of treatment withdrawal. For patients who were lost to follow-up, or those who started psychotherapeutic treatment during the study periods, time to withdrawal was censored at the date of the last assessment. In addition, the following information was collected: ADHD-RS-IV Parent:Inv., CGI-ADHD-S, WFIRS-P, RUQ, Treatment Satisfaction Questionnaire and Program Satisfaction Questionnaire. Inclusion/Exclusion criteria Patients eligible to enroll in the study were children aged 6-12 years old, who were newly diagnosed according to the DSM-IV diagnosis criteria for ADHD, and pharmacologically naive at baseline, with parents or legal guardians willing to participate in a psychoeducational program. Sample size calculation: Sample size calculations were based on the primary endpoint of time to discontinuation of treatment (any cause), assuming to detect a hazard ratio (HR) 2.07 or 0.48 with an assumption of 32% of the patients discontinuing treatment in the control group and 17% in the treatment group. A total of 360 patients were planned to be randomized. UK/W/010/pdWS/005 Page 7/37

8 Results: The study was terminated early as the number of events reported was lower than those assumed in the sample size estimation to demonstrate the primary objective: At 12 months, 13.2% patients in the intervention group and 14.3% patients in the control group had discontinued pharmacological treatment, indicating that the use of a structured psychoeducational program for parents of patients with a new diagnosis of ADHD requiring initiation of pharmacological treatment did not result in superior adherence to medication in this study. Patient disposition and reasons for discontinuation are outlined in tables 1 and 2 below. Table 1: Patient disposition study B4Z-XM-O024 UK/W/010/pdWS/005 Page 8/37

9 Table 2: Reasons for discontinuation study B4Z-XM-O024 A total of 272 patients were randomised and entered the study, of which 270 patients (144 in the intervention group, 126 in the control group) were included in the final analysis set. At baseline, Concerta (long-acting methylphenidate) was the pharmacological treatment for ADHD received by the greatest number of patients in both the intervention and the control group (47.5% and 40.5% respectively). Patients were also receiving Mediknet (long-acting methylphenidate, 24.5% and 27.6% respectively), Strattera (18.0% and 16.4% respectively) and Rubifen (methylphenidate, 10.8% and 16.4% respectively) as therapy for ADHD. Non-compliance with ADHD pharmacological treatment was low: 1.4% patients in the intervention group and 4.8% patients in the control group were reported to be non-compliant at least once. The figure below shows the Kaplan-Meier Plot for Time until Pharmacological Treatment Discontinuation over the 12 Month Study Period (= primary endpoint.) UK/W/010/pdWS/005 Page 9/37

10 For the secondary endpoints a statistically significant difference in the improvement of clinical symptoms as measured by the ADHD-RS was observed for both groups, with a stronger improvement seen in the intervention group. The MMRM of change from baseline to endpoint for the Attention-Deficit/Hyperactivity Disorder Rating Scale IV - Parent Version: Investigator Administered and Scored (ADHD-RS total) score, comparing the intervention group versus the control group, gave an estimated mean of (p=0.027; 95% CI: , ). Similarly, for the inattention and the hyperactivity-impulsivity subscores the estimated adjusted mean were (p=0.024) and (p=0.071). However, this significant difference in clinical symptoms between groups was not confirmed in an analysis based on the Clinical Global Impression-Attention-Deficit/Hyperactivity Disorder-Severity score (CGI-S: ; SE=0.197; p=0.051; CI: , ). No statistically significant between group differences in patient functioning was found using the Weiss Functional Impairment Rating (WFIRS-P) scale. More patients in the intervention group (45.1%) did maintain their original drug and dosage compared to the control group (34.1%). Serious adverse events (SAEs) were reported by 3 (2.1%) patients in the intervention group (2 with pneumonia, femur fracture) and 1 (0.8%) patient in the control group (appendicitis). AEs leading to discontinuation were reported by 2 (1.4%) of the patients in the intervention group (dystonia, glaucoma) and 7 (5.6%) of the patients in the control group (irritability, malaise, pyrexia, tachycardia, akathisia, decreased appetite, aggression). All AEs leading to discontinuation were reported by single patients. Protocol Emergent Adverse Events Reported by 5% Patients in any Group (FAS) are outlined in the table 3 below. Table 3: Protocol Emergent Adverse Events Reported by 5% Patients in any Group (FAS) In response to the RSI, the MAH presented a table of treatment-emergent adverse events by MedDRA system organ class and preferred term for patients receiving atomoxetine, patients receiving methylphenidate, and patients receiving both medications in combination. The number of patients taking methylphenidate as monotherapy was n=210, that for patients taking atomoxetine as monotherapy was n=37, and the number of patients taking the 2 medications together was n=9. The MAH concluded that the disparity in numbers of patients across groups requires caution in interpretation; and overall, it appeared that there were similar frequencies of reported adverse events for atomoxetine and methylphenidate as monotherapies, with higher rates of events for subjects taking atomoxetine and methylphenidate in combination. The overall adverse event profile for atomoxetine was not different from what is already known. UK/W/010/pdWS/005 Page 10/37

11 Assessor s comment The efficacy results from this open-label prematurely terminated trial do not merit reflection in the product information. The SOCs with the highest percentage of treatment emergent adverse events were Psychiatric disorders, Metabolism and Nutrition Disorders (decreased appetite), Nervous System Disorders, and Gastrointestinal Disorders. The review of the provided treatment emergent adverse events by SOC and preferred term does not raise any new safety concerns. IV.6 Pharmacokinetic, Efficacy, and Safety Extrapolation Analyses The main objectives of the extrapolation analyses were the following: 1) For the pharmacokinetic analyses: o To review the paediatric pharmacokinetic data for atomoxetine. o To present the pharmacokinetic data currently available for patients with lower body weights. o To perform simulations using the established population pharmacokinetic model for atomoxetine to predict the pharmacokinetic profiles for 4 to 5 year olds. 2) To perform a qualitative comparison of efficacy between 6 to 7 year olds from MAH s clinical trial data and 4 to 5 year olds from published external data. 3) To compare the safety profile between 6 to 7 year olds from MAH s clinical trial data and 4 to 5 year olds from published external data Pharmakokinetic Extrapolation Methods: As CYP2D6 activity and function are not expected to differ between 4 to 5 year olds compared to older children, the pharmacokinetic extrapolation strategy focused on differences in body weight expected for 4 to 5 year olds compared to older children. Atomoxetine is dosed using a weightbased dosing strategy (0.5 mg/kg/day as a starting dose, with 1.2 mg/kg/day as the target dose). A model was first developed using data from 420 paediatric patients (aged 7 to 15 years) from 5 clinical studies (2354 plasma concentrations). The model was validated using data from Study B4Z-MC-LYAC from 189 paediatric patients (aged 8 to 18 years): the validation was considered positive. The database used for the population pharmacokinetic analyses contained data from patients with body weights that were comparable to that expected for 4 and 5 year olds. Based on CDC Growth Charts [WWW]), the expected body weights for a 4 year old (48.5 months), 5 year old (60.5 months), and 6 year old (72.5 months) were determined. These ages were selected for simulation purposes. The body weight ranges (3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97th percentiles) for each age were determined from the growth charts. The body weight percentiles for both genders were also determined, and the values were very similar for males and females. The simulations were performed using the male body weight percentiles, since these values were nearly identical. UK/W/010/pdWS/005 Page 11/37

12 Table 4: Pharmacokinetic and Covariate Parameters in Final Population Model Studies HFBC, HFBD, HFBE, HFBF, HFBK Parameter Description Population Estimate (%SE) Inter-Patient Variability (%SE) Rate of Absorption Parameter for Ka with food (hr-1) (7.29) --- Parameter for Ka without food (hr-1) (14.6) --- Clearance a Parameter for CL/F for EM patients (L/hr) 17.4 (3.00) 44.5 % (11.4) Parameter for CL/F for PM patients (L/hr) 1.96 (5.02) Parameter for CL/F for UM patients (L/hr) 31.8 (11.6) Effect of body weight on CL/F (10.0) Effect of albumin on CL/F (35.4) Volume of Distribution b Parameter for V/F (L) 75.8 (6.06) 32.6 % (26.7) Effect of body weight on V/F (11.4) Residual Error 56.2% (5.22) Abbreviations: %SE = [(standard error of the estimate)/mean] x 100; Ka = absorption rate constant; CL/F = apparent clearance; V/F = apparent volume of distribution. a Typical value for apparent clearance (TVCL) calculation for an EM patient using the final base model: TVCL = 17.4(weight/median weight) (albumin/median albumin) b Typical value for apparent volume of distribution (TVV) calculation using the final base model: TVV = 75.8(weight/median weight) Table 5: Patients with Lower Body Weight in US Population PK Dataset of 5 Studies: Weight 25.1 kg Subject ID Age at Entry (yr) Weight at Visit (kg) CL/F (L/h) CL/F (L/h/kg) Weight 25.1 kg Abbreviations: CDC = Center for Disease Control; CL/F = apparent clearance; ID = identification; PK= pharmacokinetic; US = United States; yr = year. Results - Review of the paediatric pharmacokinetic data: Figure IV.1 shows the relationship between the pharmacokinetic parameters (CL/F and V/F) and body weight. In Figure IV.1, the Japanese patients and US patients (5 pooled studies) are combined to best illustrate this relationship and the range of atomoxetine pharmacokinetic data available. There is a significant relationship observed between CL/F and body weight, as well as between V/F and body weight. As shown, there is a wide range of body weights represented in the US and Japanese databases. UK/W/010/pdWS/005 Page 12/37

13 Figure IV.1. Apparent clearance (CL/F) and apparent volume of distribution (V/F) versus weight in US (black) and Japanese (red) paediatric patients CL/F (L/h) V/F (L) Weight (kg) Weight (kg) After including body weight in the pharmacokinetic model, there was no significant effect of age on pharmacokinetics over the age range evaluated in the population pharmacokinetic analysis, which included children as young as age 6 years (Figure IV.2). The CL/F and V/F are weight-normalised in these plots, to account for the weight effect described above. These graphs show that CL/F and V/F, after normalising for body weight, do not change significantly with age. Figure IV.2 Weight-normalised apparent clearance (CL/F) and apparent volume of distribution (V/F) versus age in US (black) and Japanese (red) paediatric patients CL/F (L/h/kg) V/F (L/kg) Age (yr) Age (yr) The MAH concludes that these results provide support for extrapolating the pharmacokinetic data to slightly younger children (ages 4 to 5 years) since age has not been shown to be a factor in the pharmacokinetics of atomoxetine, and weight differences are addressed by the weight-based dosing regimen. Assessor s comment The analysis indicates that CL/F and V/F, after normalising for body weight, do not change significantly with age in children aged 7 to 15 years. We concur with the MAH s conclusion that these results provide support for extrapolating the pharmacokinetic data to children ages 4 to 5 years old. Weight differences are addressed by the weight-based dosing regimen. UK/W/010/pdWS/005 Page 13/37

14 Results - Pharmacokinetic data for patients with lower body weights The database used for the population pharmacokinetic analyses contained data from patients with body weights that were comparable to that expected for 4 year olds ( 21.9 kg) and 5 year olds (21.9 to 25.1 kg). Although these children on atomoxetine with lower body weight were older than 4 to 5 years old, their body weights were representative of a younger child. There were 15 patients with a body weight of 21.9 kg and 27 patients at weights between 21.9 to 25.1 kg in the Japan database, and 12 patients at weights between 21.9 to 25.1 kg in the US database. Six of the Japanese patients in the 21.9 kg category also had a weight at some point during treatment in the 21.9 to 25.1 kg category, so they are also counted in with those 27 patients. The observed atomoxetine plasma concentration data for this subset of patients with lower body weights (indicative of 4 to 5 year olds) are shown in Figure 5.3 compared to the rest of the Japanese and US patients in the database (ie, those with body weights >25.1 kg). The plasma concentration data for these lower body weight patients were similar to the rest of the patients. The weight-normalised clearance values for these patients were also similar to the rest of the population (Figure 5.4). The weight-based dosing regimen for atomoxetine allows for dosing across a wide range of body weights in order to result in similar exposures across patients regardless of body weight. These results suggest that atomoxetine exposure in the body weight range expected in 4 and 5 year old paediatric patients is similar to that observed in 6 year old patients when dosed by weight. Figure 5.3. Observed atomoxetine concentration-time data for patients in Japan and US. Subgroups of body weight are shown. Japan US Dose-Weight Normalized Conc (ng/ml)/(mg/kg) Dose-Weight Normalized Conc (ng/ml)/(mg/kg) Time (h) Time (h) UK/W/010/pdWS/005 Page 14/37

15 Figure 5.4. Weight-normalised apparent clearance (CL/F) by body weight. Note: the six Japanese patients who qualify for both categories are only shown once in their lower weight category. Assessor s comment The analysis suggests that atomoxetine exposure in the body weight range expected in 4 and 5 year old paediatric patients is similar to that observed in 6 year old patients when dosed by weight. UK/W/010/pdWS/005 Page 15/37

16 Results Simulations Simulations were performed to predict the pharmacokinetic profile for each of the body weights for the 4, 5, and 6 year olds. Results of the pharmacokinetic extrapolation analyses showed that the predicted pharmacokinetic profile in 4 to 5 year olds is similar to that seen in children at least 6 years of age, see Figure below. Predicted atomoxetine concentration-time profiles for 10-mg fixed dose regimen (top panels) and 0.5 mg/kg dose regimen (bottom panels). Profiles for median (left panels) and 5th 95th percentile weights (right panels) for 4, 5, and 6 year old children are shown. 10 mg Fixed Dose Population Predicted Conc (ng/ml) Median Weight 4 year old 5 year old 6 year old Population Predicted Conc (ng/ml) th and 95th Percentile Weights Time (h) Time (h) 0.5 mg/kg Dose Population Predicted Conc (ng/ml) Median Weight 4 year old 5 year old 6 year old Population Predicted Conc (ng/ml) th and 95th Percentile Weights Time (h) Time (h) Assessor s comment Results of PK simulations indicate that the predicted pharmacokinetic profile in 4 to 5 year olds would be similar to that seen in children at least 6 years of age. UK/W/010/pdWS/005 Page 16/37

17 At the same time as submitting the responses to the RSI, the MAH supplied an addendum to the atomoxetine extrapolation report to comply with the Paediatric Investigation Plan (PIP) EMEA PIP02-11 approved in December 2011 and modified in April The addendum contains a pharmacokinetic simulation using a dose of 1.2 mg/kg and subgroup analyses for safety parameters by gender, ADHD subtype and prior stimulant use. Pharmacokinetic simulation using a dose of 1.2 mg/kg After a 1.2-mg/kg dose, the predicted pharmacokinetic profiles are superimposable for the 4-, 5-, and 6-year-old children. Assessor s comment The additional PK data are noted. As previously demonstrated for a 0.5-mg/kg dose, the predicted pharmacokinetic profiles are also superimposable for the of 1.2 mg/kg dose for 4-, 5-, and 6-yearold children. These data do not merit reflection in the product information in our view, because atomoxetine is not indicated for use in children under the age of 6 years. Comparative data for efficacy and safety Methods: The data presented are a comparison of paediatric data across four groups, as outlined in Table 6 below. Analyses were conducted using data from patients 4 to 5 years of age from 3 external studies and data from patients 6 to 7 years of age in the Lilly clinical trial database. Atomoxetine doses in these studies were generally comparable to the label recommendations. Of the 3 external studies included in the analyses, only 1 was placebo-controlled and it did not contain any patients 4 years of age. Therefore, the external placebo-controlled efficacy data are limited to 5 year olds from 1 study. Table 6: Analysis Populations for Efficacy and/or Safety Extrapolation Analyses UK/W/010/pdWS/005 Page 17/37

18 Analysis Group Lilly Paediatric Placebo- Controlled ADHD Analysis Group Lilly Paediatric Overall ADHD Analysis Group External Placebo- Controlled Dataset External Overall Dataset Age Source Description Lilly Studies Included Mean Dur. Exposure (days) children ATX 6-7 (N=393): years children 6-7 years children 5 years a children 4-5 years Lilly clinical trial database Lilly clinical trial database Kratochvil et al Kratochvil et al. 2011, 2007; Ghuman et al Data from children 6-7 years of age with ADHD, or ADHD and comorbid tics or ODD from double-blind phase of placebocontrolled studies. Autism Spectrum Disorder is excluded. Data from children 6-7 years of age with ADHD, or ADHD and comorbid tics or ODD. Autism Spectrum Disorder is excluded. Data from children 5 years of age with ADHD from an 8-week, double-blind, placebo-controlled study Data from children 4-5 years of age with ADHD from 1 placebocontrolled study and 2 open label studies 16 studies: B4Z-IT-LYCY, B4Z-JE-LYBC, B4Z-MC-HFBD, B4Z-MC-HFBK, B4Z-MC- LYAS, B4Z-MC-LYAT, B4Z-MC-LYBI, B4Z-MC-LYBX, B4Z-MW-LYCZ, B4Z-SB- LYDV, B4Z-SB-LYDW, B4Z-SO-LY15, B4Z-TW-S010, B4Z-US-LYBG, B4Z-US- LYCC, B4Z-XM-LYDM 39 studies: B4Z-BP-LYBS, B4Z-CA-S012, B4Z-CA-S013, B4Z-MC-LYAF, B4Z-EW- LYDY, B4Z-EW-LYFJ, B4Z-IT-LYCY, B4Z- IT-LYDS, B4Z-JE-LYBC, B4Z-JE-LYBD, B4Z-JE-LYDA, B4Z-KL-LYEC, B4Z-MC- LYBB, B4Z-MC-HFBC, B4Z-MC-HFBD, B4Z-MC-HFBE, B4Z-MC-HFBF, B4Z-MC- LYAB, B4Z-MC-LYAI, B4Z-MC-LYAQ, B4Z-MC-LYAS, B4Z-MC-LYAT, B4Z-MC- LYAU, B4Z-MC-LYBI, B4Z-MC-HFBK, B4Z-MC-LYBR, B4Z-MC-LYBU, B4Z-MC- LYBX, B4Z-MC-LYCL, B4Z-MW-LYCZ, B4Z-SB-LYDD, B4Z-SB-LYDV, B4Z-SB- LYDW, B4Z-SO-LY15, B4Z-TW-S010, B4Z-US-LYAV, B4Z-US-LYBG, B4Z-US- LYCC, B4Z-XM-LYDM not applicable not applicable PLA (N=186): ATX (N=1294): ATX (N=19): PLA (N=19): ATX (N=40): Analyses efficacy, safety, disposition, demographics safety, disposition, demographics efficacy, safety, disposition, demographics safety, disposition, demographics Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ATX = atomoxetine; Dur = duration; ODD = oppositional defiant disorder; PLA = placebo. a This study did not include 4 year olds. UK/W/010/pdWS/005 Page 18/37

19 Assessor s comment Below are the abstracts of the cited external studies. Neither the abstracts nor the full publications were submitted as part of this procedure. Kratochvil CJ, et al A double-blind, placebo-controlled study of atomoxetine in young children with ADHD. Pediatrics. 127(4) OBJECTIVE: To evaluate the efficacy and tolerability of atomoxetine for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in 5- and 6-year-old children. METHODS: This was an 8-week, double-blind, placebo-controlled randomized clinical trial of atomoxetine in 101 children with ADHD. Atomoxetine or placebo was flexibly titrated to a maximum dose of 1.8 mg/kg per day. The pharmacotherapist reviewed psychoeducational material on ADHD and behavioral-management strategies with parents during each study visit. RESULTS: Significant mean decreases in parent (P =.009) and teacher (P =.02) ADHD-IV Rating Scale scores were demonstrated with atomoxetine compared with placebo. A total of 40% of children treated with atomoxetine met response criteria (Clinical Global Impression-Improvement Scale indicating much or very much improved) compared with 22% of children on placebo, which was not significant (P =.1). Decreased appetite, gastrointestinal upset, and sedation were significantly more common with atomoxetine than placebo. Although some children demonstrated a robust response to atomoxetine, for others the response was more attenuated. Sixty-two percent of subjects who received atomoxetine were moderately, markedly, or severely ill according to the Clinical Global Impression-Severity Scale at study completion. CONCLUSIONS: To our knowledge, this is the first randomized controlled trial of atomoxetine in children as young as 5 years. Atomoxetine generally was well tolerated and reduced core ADHD symptoms in the children on the basis of parent and teacher reports. Reductions in the ADHD-IV Rating Scale scores, however, did not necessarily translate to overall clinical and functional improvement, as demonstrated on the Clinical Global Impression-Severity Scale and the Clinical Global Impression-Improvement Scale. Despite benefits, the children in the atomoxetine group remained, on average, significantly impaired at the end of the study. Ghuman JK et al Prospective, naturalistic, pilot study of open-label atomoxetine treatment in preschool children with attention-deficit/hyperactivity disorder. Child Adolesc Psychopharmacol. 19(2): OBJECTIVE: The aim of this study was to report preliminary data regarding effectiveness and tolerability of atomoxetine in 3- to 5-year-old preschool children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Nine boys and 3 girls (mean age = 5.0 +/ years) diagnosed with ADHD were treated with atomoxetine in an open-label pilot study. Atomoxetine was gradually titrated to a maximum dose of 1.8 mg/kg per day. RESULTS: There was a significant effect of time from baseline to end point on the parent-rated hyperactivity/impulsivity Swanson Nolan and Pelham (SNAP-IV-HI) subscale ratings (F[9, 11] = 6.32, p < ). The mean difference between the baseline and end-point parent SNAP-IV-HI scores was /- 7.3 (p = ). The rate of positive response (defined as at least a 30% reduction in the end-point parent SNAP-IV-HI scores and a Clinical Global Impressions- Improvement [CGI-I] rating of Much Improved or Very Much Improved) was 75%. The Children's Global Assessment Scale scores improved significantly over time [F(9, 11) = 6.24 p < 0.001]. The mean end-point daily dose of atomoxetine was /- 0.3 mg/kg. A high proportion (66.7%) of the preschoolers experienced side effects with atomoxetine. Side effects of defiance, tantrums, aggression, and irritability were most disconcerting to parents, and gastrointestinal complaints were UK/W/010/pdWS/005 Page 19/37

20 the most commonly reported adverse effects. One child was terminated from the study due to "chest ache." There were no changes in weight, height, or cardiovascular measures. CONCLUSION: This open-label pilot study provides preliminary evidence of effectiveness and tolerability of atomoxetine for treating ADHD in preschool children, although double-blind, randomized, placebo-controlled studies are needed to confirm this. Kratochvil CJ et al, A pilot study of atomoxetine in young children with attentiondeficit/hyperactivity disorder. J Child Adolesc Psychopharmacol OBJECTIVE: The purpose of this study was to assess the effectiveness and tolerability of atomoxetine during acute treatment of attention-deficit/hyperactivity disorder (ADHD) in 5 and 6 year olds. METHOD: Twenty two children (male n = 19, 86%) with ADHD were treated with atomoxetine for 8 weeks in a three-site, open-label pilot study. Dosing was flexible, with titration to a maximum of 1.8 mg/kg per day. Parent education on behavior management was provided as part of each pharmacotherapy visit. RESULTS: Subjects demonstrated a mean decrease of points (SD = 12.80, p < 0.001)) on the ADHD Rating Scale-IV (ADHD-IV-RS) total score, (SD = 7.48, p < 0.001) on the inattentive subscale and (SD = 7.04, p < 0.001) on the hyperactive/impulsive subscale. Clinical Global Impression-Severity (CGI-S) was improved in 82% of the children (95% CI, 66-98%) and Children's Global Assessment (CGAS) scores improved points on average (SD = 12.20, p < 0.001). The mean final dose of atomoxetine was 1.25 mg/kg per day (SD = 0.35 mg/kg per day). Mood lability was the most commonly reported adverse event (n = 12, 54.5%). Eleven subjects (50%) reported decreased appetite and a mean weight loss of 1.04 kg (SD = 0.80 kg) (p < 0.001) was observed for the group. Vital sign changes were mild and not clinically significant. There were no discontinuations due to adverse events or lack of efficacy. CONCLUSION: Atomoxetine was generally effective for reducing core ADHD symptoms in the 5 and 6 year olds in this open-label study. In addition, sensitivity analyses were run on the following subsets of the MAH s Paediatric Placebo- Controlled ADHD Analysis Group and MAH s Paediatric Overall ADHD Analysis Group Patients 6 years of age only. Patients 6 to 7 years of age who had a body weight <25.1 kg. These subpopulations were chosen for sensitivity analyses in order to provide support for the primary analyses conducted in 6 to 7 year olds but using data from patients closer to the age subset of interest (4 to 5 year olds). The upper range for body weight came from the pharmacokinetic extrapolation to match the age 4 to 5 year old weight using the CDC chart. Subject disposition: With the exception of age (as expected), patient demographics and baseline characteristics were similar between patients 6 to 7 years of age in the MAH s atomoxetine clinical trial database and patients 4 to 5 years of age from the external atomoxetine studies. A majority of patients were male and white, which is not unexpected for an ADHD population and is consistent with studies of atomoxetine in patients 6 to 18 years of age. UK/W/010/pdWS/005 Page 20/37

21 Duration of exposure in the placebo-controlled analysis groups was similar between 5 year olds from the external study (approximately 9 weeks) and 6 to 7 year olds in the MAH s studies (approximately 7 weeks). In contrast, there was a substantial difference in the duration of exposure in the overall analyses between 6 to 7 year olds in the MAH s clinical trial data (nearly 1 year) compared with the 4 to 5 year olds in the external studies (approximately 9 weeks). Table 7: Duration of Exposure and Patient-Years of Exposure Paediatric Placebo- Controlled ADHD Analysis Group (6-7 year olds) External Placebo- Controlled Dataset (5 year olds) Paediatric Overall ADHD Analysis Group (6-7 year olds) External Overall Dataset (4 to 5 year olds) ATX N=393 PBO N=186 ATX N=19 PBO N=19 ATX N=1294 ATX N=40 Duration of exposure (days) n Mean (SD) (18.41) (20.22) (10.60) (30.66) (532.61) (12.82) Min Median Max Patient-years of exposure Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ATX = atomoxetine; PBO = placebo; SD = standard deviation. Results - Efficacy In all age groups, atomoxetine treatment was associated with a greater mean improvement on the ADHDRS-IV-Parent:Inv Total Score, Inattentive Subscore, and Hyperactivity/Impulsive Subscore compared with placebo (Table 8). The magnitude of the treatment difference was greatest in the subset of patients 6 years of age (-10.16) and smallest in patients 5 years of age (-7.42). These results for total score are consistent with the magnitude of the treatment difference seen with atomoxetine in children 6 to 18 years of age (-7.75 to ) as provided in the Strattera EU Paediatric ADHD Submission and are summarised in Table 9. UK/W/010/pdWS/005 Page 21/37

22 Table 8 Summary of Mean Change from Baseline to LOCF Endpoint ADHDRS-IV-Parent:Inv (Total Score and Subscores) All Placebo-Controlled Analysis Populations ADHDRS-IV- Parent:Inv Total Score Hyperactivity/ Impulsive Subscore Paediatric Placebo- Controlled ADHD Analysis Group (6-7 year olds) ATMX PBO N=384 N= (12.79) (9.88) Paediatric Placebo- Controlled ADHD Analysis Subgroup (6 year olds) ATMX N= (12.92) PBO N= (7.85) Mean (SD) Paediatric Placebo- Controlled ADHD Analysis Subgroup (6 to 7 year olds, <25.1 kg) ATMX N= (12.80) PBO N= (9.94) External Placebo- Controlled Dataset (5 year olds) a ATMX N= (9.07) p<.001 p<.001 p<.001 p= (6.83) (5.43) (6.66) (4.54) (6.81) (5.30) PBO N= (8.09) (6.12) (4.89) p<.001 p<.001 p<.001 p= (6.85) (6.82) (6.86) (4.23) (4.94) Inattentive (5.31) (4.19) (5.52) Subscore p<.001 p<.001 p<.001 p=.006 Abbreviations: ADHDRS-IV-Parent:Inv = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored; ATMX = atomoxetine; LOCF = last observation carried forward; PBO = placebo; SD = standard deviation. a Does not include 4 year olds. Table 9 : Mean Change from Baseline to Endpoint by Treatment Group (2003 Summary of Clinical Efficacy) Primary Efficacy Measures Paediatric, Acute, Double-Blind, Placebo-Controlled Studies (HFBD, HFBK, LYAC, LYAT, LYAWa, LYBG) Patients 6 to 18 Years Scale Study Treatment N Mean Change (SD) p-value b ADHDRS-IV-Parent:Inv Total Score B4Z-MC-HFBD Atomoxetine (13.70) <.001 Placebo (11.63) B4Z-MC-HFBK Atomoxetine (12.96) <.001 Placebo (12.98) B4Z-MC-LYAC Atomox (14.01) <.001 Atomox (14.53) <.001 Placebo (10.86) B4Z-MC-LYAT Atomoxetine (12.40) <.001 Placebo (10.43) B4Z-US-LYBG Atomoxetine (14.51) <.001 Placebo (10.83) ADHDRS-IV-Teacher:Inv Total Score B4Z-MC-LYAW Atomoxetine (12.41) <.001 Placebo (9.70) Abbreviations: ADHDRS-IV-Parent:Inv = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator- Administered and Scored; ADHDRS-IV-Teacher:Inv = Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Teacher Version: Investigator-Administered and Scored; SD = standard deviation. Population: randomised patients who took at least 1 dose of drug and had a baseline and a postbaseline measurement. a Study LYAW: the ADHDRS-IV-Teacher:Inv was the primary efficacy variable. b p-value is from an F-test on differences in mean changes from baseline to endpoint scores using terms for baseline, investigator, and treatment. For LYAC, Dunnett s procedure was used to adjust for multiple comparisons. UK/W/010/pdWS/005 Page 22/37

23 Results - Safety Adverse events: Table 10 displays TEAEs occurring in at least 5% of atomoxetine-treated patients across all placebocontrolled analysis populations. Decreased appetite was very common (>10%) in atomoxetine-treated patients in all analysis populations. However, the frequency appears to be higher in the external study in 5 year olds (36.8%) compared to MAH s clinical trial data in 6 to 7 year olds (21.6%). A much higher incidence of irritability was observed in the external placebo-controlled study in 5 year olds (36.8%) compared to what was observed in analyses of MAH s clinical trial data in 6 to 7 year olds (3.6%). In addition to irritability, the following events in atomoxetine-treated patients occurred 2 more frequently in the 5 year olds than in the 6 to 7 year olds and also at a greater incidence than placebo: fatigue, sedation, and respiratory tract infection. Conversely, abdominal pain occurred 2 more frequently in the 6 to 7 year olds treated with atomoxetine than in the 5 year olds and also at a greater incidence than placebo. Table 10. Comparison (%) of Treatment-Emergent Adverse Events Occurring in at Least 5% of Atomoxetine-Treated Patients Across All Placebo-Controlled Analysis Populations a n (%) Preferred Term Patients with 1 TEAE Decreased appetite Paediatric Placebo- Controlled ADHD Analysis Group (6-7 year olds) Atomoxetine N=393 Placebo N=186 Paediatric Placebo- Controlled ADHD Analysis Subgroup (6 year olds) Atomoxetine N=133 Placebo N=72 Paediatric Placebo- Controlled ADHD Analysis Subgroup (6 to 7 year olds, <25.1 kg) Atomoxetine N=189 Placebo N=80 External Placebo- Controlled Dataset (5 year olds) a Atomoxetine N=19 Placebo N= (71.0)* 99 (53.2) 90 (67.7)* 34 (47.2) 128 (67.7)* 43 (53.8) 18 (94.7) 13 (68.4) 85 (21.6)* 8 (4.3) 33 (24.8)* 6 (8.3) 38 (20.1)* 3 (3.8) 7 (36.8)* 1 (5.3) Abdominal pain 62 (15.8)* 13 (7.0) 18 (13.5) 4 (5.6) 24 (12.7) 7 (8.8) 1 (5.3) b 1 (5.3) b Headache 51 (13.0)* 12 (6.5) 21 (15.8)* 2 (2.8) 21 (11.1) 4 (5.0) 2 (10.5) 0 Vomiting 50 (12.7)* 8 (4.3) 21 (15.8)* 4 (5.6) 19 (10.1) 3 (3.8) 3 (15.8) 0 Nausea 40 (10.2)* 4 (2.2) 13 (9.8) 2 (2.8) 18 (9.5)* 2 (2.5) 1 (5.3) 1 (5.3) Somnolence 35 (8.9)* 4 (2.2) 8 (6.0) 2 (2.8) 22 (11.6)* 0 2 (10.5) 1 (5.3) Cough 30 (7.6) 12 (6.5) 6 (4.5) 4 (5.6) 13 (6.9) 4 (5.0) 0 0 Fatigue 24 (6.1)* 3 (1.6) 8 (6.0) 2 (2.8) 5 (2.6) 0 3 (15.8) 0 Pyrexia 23 (5.9) 9 (4.8) 11 (8.3) 2 (2.8) 8 (4.2) 4 (5.0) 1 (5.3) 1 (5.3) Nasopharyngitis 22 (5.6) 10 (5.4) 8 (6.0) 1 (1.4) 14 (7.4) 5 (6.3) 1 (5.3) 0 Irritability 14 (3.6) 4 (2.2) 3 (2.3) 2 (2.8) 8 (4.2) 2 (2.5) 7 (36.8) 2 (10.5) Sedation 5 (1.3) 0 3 (2.3) 0 3 (1.6) 0 2 (10.5) 1 (5.3) Upper respiratory 16 (4.1) 5 (2.7) 5 (3.8) 2 (2.8) 6 (3.2) 1 (1.3) 2 (10.5) 0 tract infection Abbreviations: ADHD = attention-deficit/hyperactivity disorder; TEAE = treatment-emergent adverse event. Note: * = statistically significant versus placebo. a Due to the small sample size, common adverse events in the External Placebo-Controlled Dataset were considered events that occurred in at least 2 patients. b Specifically, abdominal pain upper. As in the placebo-controlled analyses, decreased appetite was very common (>10%) in atomoxetine-treated patients in all analysis populations, and was reported in a higher percentage of patients 5 years of age in the external studies compared with patients 6 to 7 years of age in the MAH s clinical trial database (44.8% versus 25.4%). Similarly, a higher percentage of 5 year olds UK/W/010/pdWS/005 Page 23/37

24 experienced irritability compared to 6 to 7 year olds (31.0% versus 8.3%). Mood altered, tearfulness, emotional disorder, and mood swings were also reported more frequently in 5 year olds (6.9% each) compared with 6 to 7 year olds (<3%). In addition to these AEs related to mood, the following events in atomoxetine-treated patients occurred 2 more frequently in the 5 year olds than in the 6 to 7 year olds: fatigue, sedation, and thirst. Conversely, AEs of headache, abdominal pain, nasopharyngitis, cough, pyrexia, oropharyngeal pain, influenza, constipation, and nasal congestion were reported 2 less frequently in atomoxetine-treated 5 year olds compared to atomoxetine-treated 6 to 7 year olds. These differences are likely attributable, at least in part, to the substantial difference in mean duration of exposure between the MAH s Paediatric Overall ADHD Analysis Group and the External Overall Dataset (352 days versus 64 days, see Table 7). Table 11: Comparison (%) of Treatment-Emergent Adverse Events Occurring in at Least 5% of Atomoxetine-Treated Patients Across All Overall Analysis Populations a n (%) Paediatric Overall ADHD Analysis Group (6-7 year olds) Atomoxetine N=1294 Paediatric Overall ADHD Analysis Subgroup (6 year olds) Paediatric Overall ADHD Analysis Subgroup (6 to 7 year olds, <25.1 kg) External Overall Dataset (5 Year Olds) a Preferred Term Atomoxetine N=444 Atomoxetine N=603 Atomoxetine N=29 Patients with 1 TEAE 1037 (80.1) 354 (79.7) 484 (80.3) 28 (96.6) Decreased appetite 329 (25.4) 118 (26.6) 132 (21.9) 13 (44.8) Headache 295 (22.8) 92 (20.7) 137 (22.7) 2 (6.9) Abdominal pain 267 (20.6) 88 (19.8) 113 (18.7) 3 (10.3) b Vomiting 226 (17.5) 76 (17.1) 99 (16.4) 4 (13.8) Nasopharyngitis 180 (13.9) 56 (12.6) 85 (14.1) 1 (3.4) Cough 172 (13.3) 65 (14.6) 78 (12.9) 0 Pyrexia 162 (12.5) 62 (14.0) 69 (11.4) 1 (3.4) Nausea 157 (12.1) 50 (11.3) 57 (9.5) 2 (6.9) Somnolence 138 (10.7) 48 (10.8) 71 (11.8) 2 (6.9) Upper respiratory tract infection 109 (8.4) 39 (8.8) 58 (9.6) 2 (6.9) Irritability 107 (8.3) 33 (7.4) 50 (8.3) 9 (31.0) Fatigue 101 (7.8) 34 (7.7) 34 (5.6) 5 (17.2) Oropharyngeal pain 89 (6.9) 23 (5.2) 41 (6.8) 0 Influenza 82 (6.3) 30 (6.8) 38 (6.3) 0 Diarrhoea 75 (5.8) 30 (6.8) 36 (6.0) 1 (3.4) Constipation 71 (5.5) 23 (5.2) 39 (6.5) 0 Nasal congestion 60 (4.6) 19 (4.3) 33 (5.5) 0 Sedation 18 (1.4) 7 (1.6) 8 (1.3) 5 (17.2) Thirst 10 (0.8) 6 (1.4) 5 (0.8) 3 (10.3) Mood altered 6 (0.5) 3 (0.7) 4 (0.7) 2 (6.9) Tearfullness 18 (1.4) 5 (1.1) 7 (1.2) 2 (6.9) Emotional disorder 20 (1.5) 5 (1.1) 4 (0.7) 2 (6.9) Mood swings 36 (2.8) 6 (1.4) 11 (1.8) 2 (6.9) Abbreviations: ADHD = attention-deficit/hyperactivity disorder; TEAE = treatment-emergent adverse event. a Excludes Ghuman et al study that solicited adverse events. b Specifically, abdominal pain upper. Ghuman et al data (which is the only study that included 4 year olds) are not included in this table because the events were not coded to preferred terms and were captured via a different reporting method (questionnaire); the data are summarised in the table below (Table 9.30). Side-effects were solicited by questionnaire, i.e. the Side Effects Rating Scale (SERS). Over half the patients ( 6 of 11 patients) 4 to 5 years of age experienced appetite loss, tearful, sad, depressed, prone UK/W/010/pdWS/005 Page 24/37