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Public Assessment Report for paediatric studies submitted in accordance
with Article 45 of Regulation (EC) No1901/2006, as amended
Alprazolam
UK/W/032/pdWS/001 Date of the Final report (Day 120):
19 November 2011
Date of finalisation of PAR 30 January 2012
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ADMINISTRATIVE INFORMATION
Invented name of the medicinal product:
See section VI
INN (or common name) of the active substance(s):
Alprazolam
MAHs: See section VI
Pharmaco-therapeutic group (ATC Code):
N05BAI2 Hypnotics and anxiolytics
Pharmaceutical form(s) and strength(s):
Immediate-release (IR) tablets 0.25 mg, 0.5 mg, 1 mg, or 2 mg, sustained-release (SR) tablets 0.5 mg, 1 mg, 2mg, or 3 mg and oral solution (drops) 0.75 mg/mL
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INDEX Executive summary and recommendation I. Introduction II. Scientific discussion
II.1 Information on the pharmaceutical formulation used in the clinical studies II.2 Non-clinical aspects 1. Introduction 2. Discussion of non clinical aspects II.3 Clinical aspects 1. Introduction 2. Clinical study 3. Literature review of published information
4. Overview of safety 5. Discussion of clinical aspects III. Rapporteur’s conclusion and recommendation on Day 89 IV. MAH response to the preliminary PdAR V. Member States overall conclusion and recommendation VI. List of medicinal products and MAH involved
ANNEX I – PROPOSED WORDING WITH NL TRANSLATION
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EXECUTIVE SUMMARY Alprazolam is a triazolo analogue of the 1,4 benzodiazepine class of central nervous system (CNS)-active compounds. Clinically, all benzodiazepines cause a dose-related CNS depressant activity varying from mild impairment of task performance to hypnosis. Alprazolam has been approved in several dose strengths for the short-term treatment of moderate or severe anxiety states and anxiety associated with depression but the licensed indications differ across countries. Alprazolam is not licensed for use in children and therefore no specific paediatric formulation is available. On 16 February 2011, one MAH submitted the studies reports from 4 trials sponsored by the MAH in paediatric patients as well as 7 published articles as relevant published literature.
Based on the available data, the MAH considers that no changes to the draft alprazolam Core Safety Profile, which is currently under review, is warranted at this time; therefore the current statement will remain unchanged as follows: Safety and efficacy of alprazolam have not been established in children and adolescents below the age of 18 years; therefore use of alprazolam is not recommended.
Based on the review of the presented paediatric data on pharmacokinetics, efficacy and safety provided by the MAH in this European work-sharing procedure under Article 45 the rapporteur considered that there is no robust evidence supporting the use of Alprazolam in paediatric patients. The currently available data from MAH-sponsored clinical trials and published medical literature remain inconclusive. No large scale, placebo controlled clinical studies have been conducted by the MAH to support the safety and efficacy of alprazolam use in paediatric patients ≤17 years of age. The majority of the MAH-sponsored studies of alprazolam XR in adolescents were terminated early due to recruitment difficulties. Therefore, no efficacy conclusions can be drawn from these data. Data derived from the published literature did demonstrate likely efficacy and safety in a few of the studies reviewed; however, most of the studies were not well controlled and the paediatric sample size of patients across studies was relatively small. In the PK study A6131003 the MAH presents the similarities found in the PK parameters after a single dose of alprazolam in healthy adolescents and young adults. The rapporteur was of the view that as the balance of risks and benefits in the paediatric population has not been established, the inclusion of the PK findings in section 5.2 “Pharmacokinetic properties” could be potentiating misleading for the prescribers. The review of the currently available paediatric data from MAH-sponsored studies, published literature, and post-marketing surveillance data did not reveal any new safety concerns in the paediatric population. The adverse events observed in a rather limited sample of adolescent subjects were considered to be similar to those observed in adult trials of alprazolam. The significant number of overdoses among adolescents is of concern but the rapporteur is of the view that this largely reflects the use of benzodiazepines with other drugs in intentional overdosing among this population. Following the circulation of the Day 89 PdAR, we received comments from 5 MSs who fully supported the rapporteur’s overall confusion and recommendation and had no further comments. The MAH was requested to provide information regarding the additional cases included in the review of the MAH’s post-marketing safety database which have not previously included in the last PSUR. Furthermore the MAH was requested to propose the paediatric wording which should be included in the PIL of all alprazolam containing preparations reflecting the available paediatric information.
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In October 2011, the MAH sent a response agreeing with comments and conclusions of the rapporteur and provided the requested information. The MAH provided a narrative line-listing of Alprazolam paediatric treatment cases not reported in a previous PSUR. The review of these cases did not identify any new safety issues or unexpected ADRs associated with the use of alprazolam in children and adolescents. The MAH also provided the paediatric wording which should be included in the PIL of all alprazolam containing preparations. SmPC and PL changes are proposed in section 4.2 <Summary of outcome>
No change
Change
New study data: <section(s) xxxx, xxxx>
New safety information
Paediatric information clarified: section 4.2
New indication
SmPC/PIL RECOMMENDATIONS Based on the review of the presented paediatric data the rapporteur considers that for all products containing alprazolam across the EU, it is recommended that SmPCs and PILs contain the following statements: SmPC wording 4.2 Posology and method of administration Paediatric patients: Safety and efficacy of alprazolam have not been established in children and adolescents below the age of 18 years; therefore use of alprazolam is not recommended. PIL wording Section 2 “What you need to know before you take alprazolam” Children and adolescents Alprazolam is not recommended for children and adolescents under the age of 18 years. The applicant is therefore requested to submit a Type IB variation to update the SmPCs and PILs of products containing alprazolam in line with the above work-sharing recommendations.
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I. INTRODUCTION On 16 February 2011, the one MAH submitted the following documents for Alprazolam in accordance with Article 45 of the Regulation (EC)No 1901/2006, as amended on medicinal products for paediatric use: Cover letter from the MAH A clinical overview of the evidence available on the safety and efficacy of the use of
Alprazolam in the paediatric population. Study reports of one completed single dose PK trial and three trials which were
prematurely terminated because of recruitment difficulties, sponsored by the MAH in paediatric patients.
7 published articles as relevant published literature. Based on the available data, the MAH considers that no changes to the draft alprazolam Core Safety Profile, which is currently under review, is warranted at this time; therefore the current statement will remain unchanged as follows: Safety and efficacy of alprazolam have not been established in children and adolescents below the age of 18 years; therefore use of alprazolam is not recommended.
Assessor’s Comment The relevant section of the PAR for PSUR procedure reads as follows: ‘Special populations: Children During the current reporting period, there were 51 cases (131 events) involving children (<17 years) representing 3.7% of all cases. The SOCs containing the greatest number of events in the pediatric population included Injury, poisoning and procedural complications (28 events), Psychiatric disorders (25), and Nervous system disorders (23). The most commonly reported adverse events were accidental drug intake by child (7 events), cardiac arrest (7), respiratory arrest (7), somnolence (6), drug abuse, and intentional drug misuse (5 events each). Among the 17 fatal cases, 9 cases were from literature articles published in Clinical Toxicology (2 patients committed suicide with multiple drug ingestion and died of cardiac and respiratory arrest. Five other cases involved patients who died of abuse/misuse of multiple medications. One other case from the literature provided limited information on a 15-year old male who died of poisoning related to alprazolam and buprenorphine. In the remaining 7 spontaneous cases, the patients died due to multiple drug ingestions or multiple drug overdoses. p-RMS’s comment : as it is mentioned in the CSP, the use of alprazolam is not recommended in children and adolescents below the age of 18 years. Information given by the CSP is considered adequate.’
II. SCIENTIFIC DISCUSSION II.1 Information on the pharmaceutical formulation used in the clinical studies Alprazolam is a triazolo analogue of the 1,4 benzodiazepine class of central nervous system (CNS)-active compounds. Clinically, all benzodiazepines cause a dose-related CNS depressant activity varying from mild impairment of task performance to hypnosis.
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Alprazolam received first regulatory approval on 12 March 1980 in Brazil. Since then, alprazolam had received marketing authorization in 125 countries and was marketed in 100 countries (including all 27 European Union countries). The MAH states that there were no actions taken regarding alprazolam for safety reasons by either a health authority or by the MAH as indicated in the latest PSUR dated 04 May 2010 (covering reporting period 01 April 2007 through 11 March 2010). Assessor’s Comment The licensed indications differ across countries. An overview of countries in which alprazolam is licensed stating the licensed indication in each country has not been provided. In the UK, alprazolam was first licensed in 1982 and is indicated for the short-term treatment of moderate or severe anxiety states and anxiety associated with depression when the disorder is severe, disabling or subjecting the individual to extreme distress. It would appear that in the US, alprazolam is indicated for panic disorder (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory ). Other licensed indications include depression (usage has not been established in depression with psychotic features, in bipolar disorders, or in “endogenous” depression), mixed anxiety-depression or depression associated with other functional or organic disease. II.2 Non-clinical aspects 1. Introduction Non-clinical studies have not been provided or summarized by the MAH on alprazolam. It is noted that the literature review conducted by the MAH did not identify preclinical studies relevant for the paediatric use of alprazolam. The USA labelling contains the following preclinical information: “When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the maximum recommended human dose) orally for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.” The UK SmPC does not contain similar information. 2. Discussion of non clinical aspects No information relevant to paediatric use of alprazolam is available in the currently approved SmPC in section 5.3. The main biological action of benzodiazepines like alprazolam consists of facilitating the inhibitory neurotransmitter action of gamma-aminobutyric acid, which mediates both pre and post synaptic inhibition in the central nervous system (CNS). This effect is not expected to be different in paediatric population. From the information submitted for this work-sharing procedure, the effect of alprazolam especially after long-term treatment on the developing CNS does not appear to have been investigated by the MAH. II.3 Clinical aspects 1. Introduction
The MAH has provided an overview of the information available regarding the paediatric use of alprazolam. This includes a short review of all available data from the 4 paediatric clinical trials conducted by the MAH and the 7 identified relevant published articles. The MAH also provided a
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summary of the alprazolam paediatric safety cases as identified in the review of the MAH’s postmarketing safety database and 3 previously submitted PSURs. 2. Clinical studies The MAH submitted four study reports:
Study A6131003: Comparison of the Pharmacokinetics of an Extended Release Formulation of Alprazolam in Healthy Normal Adolescent and Adult Volunteers
Study no A6131002: A randomized, double-blind, placebo-controlled Study of Extended Release Formulation of Alprazolam in the treatment of adolescents with a primary diagnosis of panic disorder
Study no A6131004: An open-label study to assess the safety and tolerability of Extended Release Formulation of Alprazolam in the treatment of adolescents with panic disorder or anxiety with panic attacks
Study no A6131007: A randomized, double-blind, placebo-controlled study of continuation treatment with Extended Release Formulation of Alprazolam in the treatment of adolescents with a primary diagnosis of panic disorder
All trials except the PK trial (A6131003) were prematurely terminated due to recruitment difficulties.
Protocol A6131003. Comparison of the Pharmacokinetics of an Extended Release Formulation of Alprazolam in Healthy Normal Adolescent and Adult VolunteersMethods
Objective The purpose of this study was to estimate the pharmacokinetics and the safety and tolerability of single doses of Extended Release Formulation of Alprazolam in adolescent and adult healthy volunteers.
Study design This was a randomized, open-label, single-dose, 2-period crossover study.
Study population /Sample size Twelve adolescent healthy volunteers (aged 13-17 years) and 12 adult healthy volunteers (aged 20-45 years) were recruited. Health status was determined by a detailed medical history, full physical examination (including blood pressure and heart rate measurement), 12-lead electrocardiogram (ECG), and clinical laboratory tests.
Treatments Patients received single doses of Alprazolam 1 mg or 3 mg tablets in a crossover fashion. They all underwent a 7-day washout period between doses.
Outcomes/endpoints
Pharmacokinetic assessment Blood samples were collected at 0 (just prior to dosing), 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours post-dose on study Day 1 of each study period. The following PK parameters were determined for alprazolam: AUC(0-t), AUC(0-∞), Cmax, Tmax, and t½. Also AUC(0-t), Cmax, and Tmax were determined for the 2 major metabolites α-hydroxyalprazolam and 4-hydroxy-alprazolam.
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Safety assessment Safety assessments included clinical laboratory tests, vital signs, and adverse event monitoring.
Statistical Methods Log-transformed dose-normalized AUC(0-∞) and Cmax were analyzed by mixed effects analysis of variance (ANOVA), with age-group, dose, and period effects and interaction terms, period*dose and age-group*dose, considered fixed and subject considered random. For the comparison between the adults and adolescents, 95% confidence intervals on the adjusted mean ratio of AUC(0-t) and AUC(0-∞) for the adolescents vs the adults was computed. For the dose comparisons with each group, the 90% confidence interval on the dose adjusted mean ratio of AUC(0-t), and AUC(0-∞) for the 3 mg vs the 1 mg dose was compared to the equivalence limits (80, 125%). An exploratory regression analysis was performed for the adolescent subset to assess the effects of age, weight, and sex on the endpoints AUC(0-∞) and Cmax. Vital signs were summarized using descriptive statistics (means and change from baseline).
Results Twenty-four patients entered and completed dosing, of which 12 were adolescents. The tables below summarise the results of the primary PK analysis for Alprazolam 1 mg, Alprazolam 3 mg, and doses combined: within- and between-age-group comparisons. Table 1a SUMMARY OF STATISTICAL ANALYSES OF ALPRAZOLAM PK PARAMETERS FOR DOSES 1MG,3MG AND DOSES COMBINES: BETWEEN AGE GROUPS COMPARISON
Table 1b SUMMARY OF STATISTICAL ANALYSES OF ALPRAZOLAM PK PARAMETERS FOR ADOLESCENTS AND ADULTS; WITHIN AGE GROUPS COMPARISON
The MAH concludes that AUC(0-∞) and Cmax results demonstrate dose proportionality of alprazolam after single 1 and 3 mg doses for both adolescents and adults. Mean concentration-time profiles were similar for both groups. Compared with adults, relative AUC(0-∞) and Cmax in adolescents, expressed as ratios of the estimated geometric means for both dose levels, were 115% and 111%, respectively. These differences are not of clinical relevance.
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Safety results There were no deaths, dose reductions, temporary or permanent withdrawals in the study. Overall, there were a total of 31 treatment-emergent adverse events (AEs) reported by 20 patients. All AEs were either mild (N=13) or moderate (N=18) in severity. Of the moderate adverse events, the majority occurred in the nervous body system and included 14 cases of somnolence and 1 case of dizziness. Somnolence occurred in a dose-related manner for both the adolescents and adults. All cases resolved without intervention.
Assessor’s Comment In this study the MAH presents the similarities found in the PK parameters after a single dose of alprazolam in healthy adolescents and young adults. The rapporteur is of the view that as that the balance of risks and benefits in the paediatric population has not been established (see below), the inclusion of the PK findings in section 5.2 “Pharmacokinetic properties” could be potentiating misleading for the prescribers. Regarding the safety of the paediatric use of alprazolam, the single oral dose appears to be well tolerated and no unusual AEs have been reported during this study.
Protocol A6131002. Randomized, Double-Blind, Placebo-Controlled Study of Extended Release Formulation of Alprazolam in the Treatment of Adolescents With A Primary Diagnosis of Panic Disorder.
Objective The primary objective of this study was to assess the efficacy of alprazolam extended release (XR) in adolescents with a primary diagnosis of panic disorder with or without agoraphobia. Secondary objectives were to assess the safety and tolerability of alprazolam XR in adolescents with panic disorder and to assess the pharmacokinetic profile of alprazolam XR in adolescents with panic disorder.
Study design This was a 6-week, multicenter, randomized, double-blind, placebo controlled, flexible-dose study of alprazolam XR (1-6 mg/day) for the acute treatment of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSMIV- TR) panic disorder, with or without agoraphobia, in adolescents (age range, 13-17 years) in an outpatient setting. The 6 weeks of acute treatment were preceded by a 3- to 14-day washout period with no study drug or placebo. Patients who completed 6 weeks of treatment and who, in the opinion of the investigator, could have benefited from continued study treatment, were evaluated for entry into an 18-week continuation study (Protocol A6131007). Patients who were not eligible for entry into the continuation study, or who were eligible but elected not to participate, were tapered off study drug at a rate of 1 mg every 7 days for up to a 6-week taper period.
Study population /Sample size Patients were to have a primary DSM-IV-TR diagnosis of panic disorder with or without agoraphobia based on the MINI Kid. Patients were to have an average of 1) at least one 4-symptom panic attack per week over the last 4 weeks before screening; 2) at least one 4-symptom panic attack per week over the last 4 weeks before baseline; and 3) at least one 4-symptom panic attack in the 7 days prior to baseline. Enrolled patients were
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randomized in a 1:1 ratio to 1 of the 2 treatment groups: alprazolam XR or placebo. The planned number of patients was 228 (114 per treatment group). At the time of study termination, 16 patients had been randomized and 15 patients had been treated. Notification that the alprazolam XR paediatric program was cancelled before enrolment for this study could be completed was sent to the FDA on 1 September 2004. All enrolled patients at the time of study termination were given the option to complete the study (although some subjects were withdrawn), and no additional patients were enrolled.
Treatments A flexible dosing strategy was used with treatment started at a daily dose of 1 mg (or placebo equivalent) for the first 7 days. Thereafter the daily dose was titrated at a maximum rate of 1 mg (or placebo equivalent) every 7 days up to a maximum dosage of 6 mg (or placebo equivalent) for lack of response, and in the absence of dose-limiting adverse events. No further increases in daily dosage were permitted after Day 36; dosage reductions were permitted if required for tolerability.
Outcomes/endpoints
Efficacy assessment Primary efficacy measures were change in weekly frequency of 4-symptom panic attacks as recorded in a subject diary and change in Panic Disorder Severity Scale for Adolescents (PDSS-A) total score. Secondary efficacy measures included: Weekly change in PDSS-A total score; Clinical Global Impression (CGI)-Severity scale; CGI-Improvement scale; PDSS-A item scores; Hamilton anxiety rating scale (HAM-A); Children’s Depression Rating Scale (CDRS-R); Pediatric Quality of Life, Enjoyment, and Satisfaction Questionnaire (PQ-LES-Q). Cognitive and memory effects of study drug were evaluated by the Digit Symbol-Coding Test and immediate and delayed free recall of a word list. Safety assessment Safety was assessed through adverse events, laboratory assessments, vital signs, electrocardiograms and physical examinations. Adverse events due to study drug discontinuation during the taper period were evaluated using the Rickels Physician Withdrawal Checklist (PWC). PK assessment Population PK analyses were planned based on plasma alprazolam XR samples obtained at 3 time points during the 6 weeks of study treatment. However due to the limited number of samples collected in this study analyses could not be carried out.
Statistical Methods The planned statistical power to detect a mean difference of 3 in the weekly number of panic attacks was based on a planned sample size of 114 subjects per group. Because this study was terminated prematurely, no formal statistical testing was conducted.
Results Fifteen subjects (8 in the alprazolam XR group and 7 in the placebo group) had baseline and post-baseline efficacy data for the primary efficacy variables.
Efficacy results At baseline, the mean (SD) number of panic attacks since the previous visit was 6.00 (3.38) in the alprazolam XR group and 18.00 (10.89) in the placebo group. At endpoint,
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the mean (SD) number of panic attacks since the previous visit was 6.63 (8.21) (change of 0.63) in the alprazolam XR group and 11.57 (11.16) (change of -6.43) in the placebo group. At baseline, the mean (SD) PDSS-A total score was 14.00 (3.21) in the alprazolam XR group and 17.14 (3.13) in the placebo group. At endpoint, the mean (SD) PDSS-A total score was 9.38 (5.21) (change of -4.63) in the alprazolam XR group and 12.00 (7.55) (change of –5.14) in the placebo group.
Safety results Most participants had at least 1 treatment-emergent adverse event (regardless of causality; 7 of 8 in the alprazolam XR group and 5 of 7 in the placebo group). All but 1 patient (in the placebo group) who reported adverse events had at least 1 adverse event that was considered related to treatment. The most commonly reported adverse events were related to the nervous system or were psychiatric in nature. Adverse events reported by more than 1 patient in either treatment group were dizziness, headache, sedation, and somnolence (Table 2). Most of these adverse events were judged by the investigators as mild or moderate in severity. In the alprazolam XR group, there was 1 severe case of dizziness and 1 severe case of sedation. In the placebo group, there was 1 severe case of headache. Table 2: Treatment-Emergent Adverse Events Occurring in More than One Subject (All Causalities) - Safety Population
Two patients in the alprazolam XR group (1 of them also had a dosage reduction) and 1 patient in the placebo group discontinued treatment due to adverse events. One additional patient in the placebo group had a dosage reduction or temporary discontinuation of study medication due to adverse events. No serious adverse events or deaths occurred during this study. A total of 6 and 4 patients in the alprazolam XR and placebo groups, respectively, had post-baseline clinical laboratory data. One patient (in the alprazolam XR group) had a clinically significant post-baseline laboratory abnormality (blood in the urine during treatment). There were no notable changes in either treatment group in the median changes from baseline to the last measurement in clinical laboratory values. No patient discontinued treatment due to an adverse event related to a laboratory abnormality. There were no notable changes in blood pressure, pulse, or body weight from baseline to the final visit. There were no clinically significant abnormal ECG findings.
Assessor’s Comment This study was terminated early with less than 10% of planned number of patients enrolled. The rapporteur is of the view that no efficacy conclusions on the use of alprazolam in adolescents with panic disorders can be drawn from these data. Regarding safety, the rapporteur agrees with the MAH’s overall conclusion that the adverse events observed in this limited sample of adolescent patients were similar to those observed in adult trials of alprazolam XR in panic disorder.
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Protocol A6131007. A Randomized, Double-Blind, Placebo-Controlled Study of Continuation Treatment with Extended Release Formulation of Alprazolam in the Treatment of Adolescents with a Primary Diagnosis of Panic Disorder
Objective The primary objectives of this study were to assess the long-term (6-month) safety and tolerability of alprazolam extended release (XR) in adolescents with panic disorder with or without agoraphobia. The secondary objective was to assess the efficacy of alprazolam XR during long-term (6-month) treatment.
Study design/Study population This was an 18-week, double-blind, placebo-controlled continuation study in which patients who had just completed treatment in a 6-week acute efficacy study (Protocol A6131002) continued their double-blind, flexible-dose treatment with alprazolam XR (1-6 mg/day) or placebo. Patients were to remain eligible for the study according to the exclusion criteria of Study A6131002, with the exception that patients were allowed to undergo cognitive-behavioural or other panic-specific therapy and any other psychotherapy. The 18 weeks of double-blind study treatment was followed by a 1- to 6-week double-blind taper off study drug. Due to recruitment difficulties in this adolescent population, the clinical program for alprazolam XR was cancelled and this study was terminated. The planned enrolment was 150 patients. At the time of study termination, 3 patients had entered this study and all were withdrawn from the study at the sponsor’s request before completion of 18 weeks of treatment.
Treatments Patients were to continue to take the same dosage of alprazolam XR (or matching placebo) that they were taking when they completed Study A6131002. Patients taking less than 6 mg/day (or placebo equivalent) who failed to show a satisfactory clinical response (in the opinion of the investigator) since the previous visit, and who were free of dose-limiting adverse events, could have their dosage titrated upward by 1 mg/day (or placebo equivalent). Upward daily dosage titration of 1 mg (or placebo equivalent) was allowed, up to a maximum daily dosage of 6 mg/day (or placebo equivalent). Patients who were unable to tolerate the previous dosage level of alprazolam XR or placebo equivalent could have had their daily dosage reduced, based on the clinical judgment of the investigator.
Outcomes/endpoints
Efficacy: There were no primary efficacy measures defined for this study. Secondary evaluations included: the Panic Disorder Severity Scale-Adolescent version (PDSS-A) total and item scores; CGI-Severity scale (CGI-S) and CGIImprovement scale (CGI-I); Hamilton Anxiety Rating Scale (HAM-A); Pediatric Quality of Life, Enjoyment, and Satisfaction Questionnaire (PQ-LES-Q); and Childhood Depression Rating Scale-revised (CDRS-R). Cognitive and memory effects of study drug were evaluated by the Digit Symbol-Coding Test and immediate and delayed free recall of a word list. Pharmacokinetic: Population pharmacokinetic (PK) analyses were planned based on plasma alprazolam XR samples obtained at Weeks 12 and 24 of study treatment. Safety: Safety was assessed through adverse events, laboratory assessments, vital signs, electrocardiograms (ECGs), and physical examinations. Adverse events due to study drug discontinuation during the taper period were evaluated using the Rickels Physician Withdrawal Checklist (PWC).
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Results Efficacy and PK analysis have not been performed due to small number of patients included in this study, There were no treatment-emergent adverse events reported in the alprazolam XR-treated subject. Clinical laboratory data were available for the alprazolam XR-treated subject only. Most values were within normal range for this subject. This subject had the presence of ketones and haemoglobin in the urine on Day 45 (last day of treatment) that were both considered clinically significant (no subsequent values were reported).
Assessor’s Comment In this study only one adolescent was treated with alprazolam and therefore no robust information regarding the safety or the effect of the treatment in paediatric patients with panic disorders has been generated.
Protocol A6131004. An Open-Label Study to Assess the Safety and Tolerability of Extended Release Formulation of Alprazolam in the Treatment of Adolescents with Panic Disorder or Anxiety with Panic Attacks
Objective The primary objectives of this study were to assess the long-term (6-month) safety and tolerability of alprazolam extended release (XR) in adolescents with panic disorder, with or without agoraphobia, or in anxiety disorder with panic attacks. The secondary objectives were to assess the efficacy of alprazolam XR during long-term (6 month) treatment and assess the population pharmacokinetics (PK) of alprazolam XR, and the relationship between alprazolam XR plasma concentrations and efficacy outcomes.
Study design/Study population This was a 6-month, open-label, flexible-dose study of alprazolam XR (1-6 mg/day) for the treatment of DSM-IV-TR panic disorder (with or without agoraphobia), or anxiety disorder (generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, separation anxiety, anxiety-NOS) with panic attacks, in adolescent outpatients aged 13 to 17 years. The 6 months of study treatment were preceded by a 7-day washout period with no drug or placebo, and were followed by a 1- to 6-week taper off study drug. This study was terminated early due to recruitment difficulties in this population. No additional patients were enrolled after the time of study termination and no patients completed the study. The planned number of enrolled patients was 300. At the time of study termination, 46 patients had been enrolled and 45 patients had been treated with alprazolam XR.
Treatments Patients were to take alprazolam XR 1 mg/day for 7 days. All upward dose titrations during the course of study treatment were made based on the clinical judgment of the investigators, and were not to exceed 1 mg increases every 7 days, up to a maximum of 6 mg/day. Dosage reductions were allowed based on clinical judgment of the investigators. Patients who were unable to tolerate a 1 mg daily dose of alprazolam XR were withdrawn from the study.
Outcomes/endpoints
Efficacy: No primary efficacy measures were defined for this study. Secondary efficacy measures included the Panic Disorder Severity Scale-Adolescent version (PDSS-A) total
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and item scores; CGI-Severity (CGI-S) scale; CGI-Improvement (CGI-I) scale; Pediatric Quality of Life, Enjoyment, Satisfaction Questionnaire (PQ-LES-Q); Hamilton Anxiety Rating Scale (HAM-A); and Childhood Depression Rating Scale, Revised (CDRS-R). Pharmacokinetic: blood samples for determinations of plasma alprazolam XR concentrations were obtained at Weeks 12 and 24 of study treatment. Safety: Safety was the primary objective of this study and was assessed through adverse events, laboratory assessments, vital signs, electrocardiograms (ECGs), and physical examinations. Other: Effects of study drug on cognitive function and memory effects were evaluated by the Digit Symbol-Coding Test and immediate and delayed free recall of a word list. Adverse events due to study drug discontinuation during the taper period were evaluated using the Rickels Physician Withdrawal Checklist (PWC).
Results Efficacy and PK analysis have not been performed due to small number of patients included in this study. No deaths occurred during this study. Two patients had serious adverse events during treatment (therapeutic agent toxicity [investigator term: benzodiazepine intoxication], anxiety disorder, depression, and disinhibition; and overdose). One of these patients had serious adverse events that were considered related to study medication (therapeutic agent toxicity, anxiety disorder, depression, and disinhibition); both patients recovered. The overdose led to permanent discontinuation of study medication and the patient recovered on the same day; the investigator considered the event as due to “other – intentional overdose by subject.” An additional patient experienced a serious adverse event post-therapy (factitious disorder). Eight patients discontinued due to adverse events, 7 of whom had at least 1 adverse event that was considered related to treatment. Of the 45 patients in the safety population, 37 had adverse events regardless of causality and 28 had adverse events considered related to treatment. A summary of all adverse events (all causalities) reported by more than 1 patient is provided in Table 3. Most adverse events were mild or moderate in severity. Table 3: The Most Commona Treatment-Emergent Adverse Events (All Causalities)
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Treatment-related adverse events occurring in more than 1 patient were somnolence (n=11), fatigue (n=5), sedation (n=4), lethargy (n=3), dizziness (n=3), and depression (n=2). Clinically significant abnormal laboratory values were reported in 1 patient with elevated monocytes (>1.2 times the ULN), 2 patients with ketones in the urine, 1 patient with protein in the urine, and 4 patients with blood in the urine. There were no notable changes in median clinical laboratory test values from baseline to last observation. No patients discontinued treatment due to an adverse event related to a laboratory abnormality. There were no notable median changes from baseline to last observation in blood pressure, pulse, or body weight. There were no clinically significant abnormal ECG findings.
Assessor’s Comment This 6-month open-label study of alprazolam in adolescents with panic disorder was terminated prematurely, with 15% of the planned number of subjects enrolled and no subjects completing the study. Therefore, no robust safety or efficacy conclusions can be drawn from these data. 3. Literature review of published information A comprehensive literature search to identify published articles and abstracts relevant to alprazolam use in the paediatric population was performed by the MAH. The following 7 articles with a paediatric interest were identified by the MAH as supporting information to the conducted clinical trials: 1. Anderson BJ, Exarchos H, Lee K, et al. Oral premedication in children: a comparison of
chloral hydrate, diazepam, alprazolam, midazolam and placebo for day surgery. Anaesth Intensive Care 1990;18(2):185-93.
2. Bernstein GA, Garfinkel BD, Borchardt CM. Comparative studies of pharmacotherapy for school refusal. J Am Acad Child Adolesc Psychiatry 1990;29(5):773-81
3. DeVane CL, Hill M, Antal EJ. Therapeutic drug monitoring of alprazolam in adolescents with asthma. Ther Drug Monit 1998; 20(3):257-60.
4. Ferguson HB, Simeon JG. Evaluating drug effects on children's cognitive functioning. Progr NeuroPsychopharmacol Biol Psychiatry 1984;8(4-6):683-6.
5. Pfefferbaum B, Overall JE, Boren HA, et al. Alprazolam in the treatment of anticipatory and acute situational anxiety in children with cancer. J Am Acad Child Adolesc Psychiatry 1987;26(4):532-5.
6. Simeon JG, Ferguson HB, Knott V, et al. Clinical, cognitive, and neurophysiological effects of alprazolam in children and adolescents with overanxious and avoidant disorders. J Am Acad Child Adolesc Psychiatry 1992;31(1):29-33.
7. Simeon JG, Ferguson HB. Alprazolam effects in children with anxiety disorders. Can J Psychiatry 1987;32(7):570-4
Assessor’s Comment The MAH included these studies as supportive documentation in the clinical trial package. It is noted that the literature research methodology and article selection criteria used by the MAH were not identified in the overview report. DeVane CL, Hill M, Antal EJ. Therapeutic drug monitoring of alprazolam in adolescents with asthma. Ther Drug Monit 1998; 20(3):257-60.
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Children and adolescents with severe asthma frequently experience anxiety or depression with anxiety, which can undermine their response to treatment. In addition, these patients often receive theophylline and a variety of adrenergic stimulants, which can exacerbate or worsen anxiety. Such children occasionally are candidates for treatment with anxiolytic therapy. There is a paucity of drug disposition data in adolescents for benzodiazepines, the most frequently used antianxiety drugs. The major objective of this study was to collect PK data of alprazolam in adolescents under clinical conditions to compare the drug's disposition in this moderately to severely ill population to disposition parameters in adults. In addition, the tolerance to alprazolam in this population who typically receives multiple-drug therapy was also monitored. Six adolescents whose aged ranged from 14 through 17, all of whom had chronic asthma participated in the study. Alprazolam was indicated for the presence of anxiety. The dosage ranged from 0.75 to 3.0 mg/day. The number of blood samples collected per patient ranged from 2 to 10. Alprazolam was well tolerated in five of the six patients. The dosage administered (range 0.75 to 3.0 mg/day) is similar to that commonly prescribed in adults for treatment of symptoms of anxiety. In these patients, as in adults, the dosage was titrated according to clinical response. One patient complained of excessive sedation. However, alprazolam plasma concentration in this patient was not substantially higher compared with the concentration measured in other patients. Thus, differences in benzodiazepine tolerance are likely to be related to factors more complex than plasma drug concentration alone. In one patient administered concurrent therapy with troleandomycin, a recognized cytochrome 3A4 inhibitor, alprazolam plasma concentration was markedly elevated. Overall, the disposition data of alprazolam in adolescents was consistent with data previously reported in adults. The authors concluded that Alprazolam appeared to be safe and effective for use in the management of symptoms of anxiety in adolescents with asthma. Assessor’s Comment There are limited paediatric PK data in the published literature. The authors of this study concluded that overall, the disposition data of alprazolam was consistent with data previously reported in adults. This is also in line with the MAH’s conclusions drawn from the sponsored PK trial (A6131003). It is known that changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of conditions including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients as there is a reduced clearance of the drug and, as with other benzodiazepines, an increased sensitivity to the drug in the elderly. The current approved SmPC does not contain any information regarding the PK profile of alprazolam in paediatric patients. Simeon JG, Ferguson HB, Knott V, et al. Clinical, cognitive, and neurophysiological effects of alprazolam in children and adolescents with overanxious and avoidant disorders. J Am Acad Child Adolesc Psychiatry 1992;31(1):29-33. In a double-blind, placebo-controlled study, the efficacy and safety of alprazolam was investigated in childhood and adolescent anxiety disorders. The study group consisted of 30 outpatients (ages ranged from 8.4 to 16.9 years, mean 12.6years) diagnosed with overanxious or avoidant disorders. All patients received placebo for 1 week, then alprazolam or placebo (randomly assigned and double-blind) for 4 weeks. The initial dose of alprazolam was either 0.25 mg for patients under 40 kg of body weight or 0.50 mg for those over 40 kg of body weight. Upward titration was at 2-day intervals. The maximum daily dosage permitted was 0.04 mg/kg/day and based on screening weight, could range from 1.04 mg to 3.5 mg/day. Average maximum dose was 1.57 mg by the end of the fourth week. Evaluations included clinical, laboratory, cognitive, and qualitative EEG measurements. Clinical global improvements were
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rated on a scale as no change (4), minimally improved (3), much improved (2) or very much improved (1). Results on study admission demonstrated the degree of global illness was severe in 3 patients, marked in 9 and moderate in 18. With AP and placebo, respectively, improvements in the overanxious (n = 13 vs. 8) and the avoidant (n = 4 vs. 5) groups were very much in 1 patient each, much in 7 vs. 4, minimal in 7 vs. 3, no change in 2 vs. 3 and worse in 0 vs. 1. In the overanxious group, AP showed a slightly greater mean improvement than the placebo group (2.69 vs. 2.85). Following tapering the AP group showed a slight relapse (2.9) while the placebo group continued to improve (2.42). With AP, the avoidant disorder group showed a greater improvement than placebo (2.5 vs. 3). Following tapering, the AP group relapsed (3) while the placebo group showed no further change (3). Self-ratings indicated improvements of worry and negative-peer factors. AP altered EEG. The placebo group showed evidence of decreasing cognitive efficacy relative to AP. AP was well tolerated with few, mild transient side-effects. On a clinical global rating, there was no statistical difference between alprazolam and placebo. Overall, the results showed that alprazolam is safe for use with children and adolescents with anxiety disorders. The general significance of the clinical data reported in this trial is limited by the small number of patients, the short duration of drug administration, and the relatively low dosages. The authors state that future research examining the role for alprazolam in child and adolescent disorders should distinguish between subtypes of anxiety disorders (overanxiousness, avoidant, separation, panic) and employ longer trials with a wider dosage range. Assessor’s Comment Simeon et al reported their results from a double-blind, placebo controlled study in 30 patients aged 8 to 16 years diagnosed with overanxious or avoidant disorder. On clinical global rating, there was no statistical difference between alprazolam and placebo although alprazolam was well tolerated. This finding is a marked contrast to the effects attributed to the drug in studies with adults. However the small sample size precludes robust conclusion to be drawn regarding the paediatric use of alprazolam in these indications. Anderson BJ, Exarchos H, Lee K, et al. Oral premedication in children: a comparison of chloral hydrate, diazepam, alprazolam, midazolam and placebo for day surgery. Anaesth Intensive Care 1990;18(2):185-93. A double-blind study consisting of 339 randomly selected children investigated the effects of several premedicants on the preoperative and postoperative behaviour of children who underwent day-stay surgery. Patients were allocated into two groups. Group 1 consisted of 165 children aged between 6 and 47 months. Group 2 consisted of 174 children aged four years and older to a body weight of 50 kg. Each child received one premedicant. Both groups included alprazolam 0.005 mg/kg, midazolam 0.3 mg/kg and placebo. In addition, Group 1 included chloral hydrate 40 mg/kg and Group 2 diazepam 0.25 mg/kg. Chloral hydrate produced superior conditions (more patients calm or asleep) at induction of anaesthesia. Postoperative behaviour and incidence of vomiting were similar for all drugs. No premedicant reduced anxiety in the older group. The time to awaken postoperatively with diazepam was longer than with placebo. Alprazolam and midazolam were unpalatable for children over four years and conferred no advantage over placebo. Assessor’s Comment Anderson et al reports results from a double-blind trial comparing alprazolam with other drugs as a premedication for day-case surgery in children aged 6 months and above. The randomisation procedure is not described in this paper. Study medication appears to have consisted of crushed tablets in raspberry juice prepared by the pharmacy. The alprazolam
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formulation was unpalatable to children over the age of four years. More importantly this study failed to demonstrate an advantage of alprazolam over placebo in any age group with no alteration of behaviour noted even at peak plasma concentrations; it is therefore concluded that based on this study its use as premedicant in children is unwarranted. Bernstein GA, Garfinkel BD, Borchardt CM. Comparative studies of pharmacotherapy for school refusal. J Am Acad Child Adolesc Psychiatry 1990;29(5):773-81 Two studies compared alprazolam and imipramine in the treatment of school refusal. In an open label study (N = 17; 9 males, 8 females; mean age 14.17 ± 1.92 years, with the range from 9.5-17 years), two-thirds of the subjects completing a trial in both the alprazolam and imipramine groups showed moderate to marked global improvement in symptoms of anxiety and depression. In the double-blind, placebo-controlled study (N = 24; 13 males, 11 females; mean age 14.12 ± 1.98 years, with the range from 7.66-17.58 years), post-treatment scores calculated as change from baseline on the Anxiety Rating for Children were significantly different (p = .03) among the three treatment groups, with the active medication groups showing the most improvement. Additionally, on all depression rating scales, similar trends were evident with the alprazolam and imipramine groups demonstrating greater improvement than the placebo group. However, analyses of covariance (with pre-treatment scores as the covariates) showed no significant differences among the three treatment groups on change in anxiety and depression scales. Thus, the authors state that additional research is needed to determine whether trends in this study are explained by drug effect or baseline differences on rating scales. Assessor’s Comment This study has several limitations including the small sample size (which became smaller by week 8 due to subjects dropping out), the documented large standard deviations of the treatment’s effects and variability of the baseline characteristics of the study populations. The lack of any significant differences among the three treatment groups on change in anxiety and depression scales limits the efficacy conclusions that can be drawn from this study as the authors acknowledged that further research is needed. Pfefferbaum B, Overall JE, Boren HA, et al. Alprazolam in the treatment of anticipatory and acute situational anxiety in children with cancer. J Am Acad Child Adolesc Psychiatry 1987;26(4):532-5. A population of childhood cancer patients who undergo scheduled, periodic, stressful events such as bone marrow aspirations and spinal taps was chosen as a model for the investigation of the use of alprazolam in the treatment of anticipatory and acute situational anxiety in children. An open-label dose-ranging study was completed on 13 children with leukaemia or lymphoma ranging in age between 7 and 16 years. Initial alprazolam doses of 0.005 mg/kg or lower based on the child’s weight, and doses were increased for successive procedures depending on efficacy and side effects. The maximum dose allowed was 0.02 mg/kg/dose or 0.06 mg/kg/day. Because this was an early trial of a drug not approved for use in children, doses were low. Of major importance this study demonstrates that antianxiety agents such as alprazolam may have a place in the treatment of children who experience anticipatory and acute situational anxiety and panic. Several of the children in this study responded to very low doses of alprazolam. Of course, concern about possible placebo effect must be considered in any open-label study. In addition, the physical status and cancer treatment protocols of these children may have altered their metabolism of the drug. Even so, some children may require high doses of such antianxiety agents or may be nonresponsive even at higher doses for individual undiscerned biological or psychological reasons. Nonetheless, safe efficacious use of alprazolam was demonstrated and
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indicates that antianxiety agents may have a useful purpose for brief intervention situations in children. Assessor’s Comment Pfefferbaum et al report an open-label trial in 13 children with leukaemia treated with alprazolam for 3 days prior to a stressful procedure. The authors argued that the scheduled medical procedures are known periodic stressors for which acute intervention could be considered beneficial in children. The clinical situation described here in children on leukaemia treatment was considered as a model for anticipatory and acute situational anxiety. However the distinction between anticipatory and acute situation anxiety warrants further discussion. Overall this is a rather small interventional study with no clear protocol regarding the optimal time or the needed dose of alprazolam in these children. Simeon JG, Ferguson HB. Alprazolam effects in children with anxiety disorders. Can J Psychiatry 1987;32(7):570-4 Children with overanxious and/or avoidant disorder (DSM-III) were treated with alprazolam to determine its safety, clinical and cognitive effects. Ten male and two female patients (age range 8.8 to 16.5 years; mean 11.5) participated in an open clinical trial consisting of a baseline placebo period (1 week), alprazolam therapy (4 weeks), a drug- tapering period (1 week), and a post-drug placebo period (1 week). There was a drug-free follow-up approximately 4 weeks after termination of the study. Dosages were individually adjusted and the daily maximum ranged from 0.50 mg to 1.5 mg. Evaluations included clinical assessments, parent, teacher, and self ratings, and cognitive tests. Clinical global improvement with alprazolam therapy was marked in 1 patient, moderate in 6, minimal in 4, and none in 1. Clinician ratings indicated significant improvements of anxiety, depression, and psychomotor excitation. Parent questionnaires indicated significant improvements of anxiety and hyperactivity while teacher questionnaires showed significant improvement of an anxious-passive factor. Significant improvements in the paired associate learning tasks, maze task and the block design tasks were maintained after drug withdrawal suggesting a practice effect. Adverse effects were infrequent, mild and transient. There were no clinically significant changes of laboratory values, blood pressure, pulse or respiration during the 4 weeks of alprazolam administration. Body weight increased significantly (mean increase was 0.87 kg). One of the most frequent and noticeable changes in the patients was an improvement in sleep problems reported by parents. In this trial, children who suffered predominantly from inhibitions, shyness and nervousness, and had a good premorbid personality, seemed to show a good response and continued improvement after the drug was withdrawn. In contrast, children with poor premorbid personality development and poor family background showed more negative disinhibiting drug effects (for example, increased aggression and impulsivity), particularly with higher dosages, and relapsed after drug discontinuation. Thus, it appears that benzodiazepine-induced disinhibition of suppressed behaviour can be either therapeutic or negative, and may depend on genetic predisposition, personality dynamics, aggressivity and social norms. The results of this trial suggest that alprazolam is a safe and perhaps effective medication for the treatment of anxiety disorders and sleep problems in children. Based upon this study data, the authors recommend that controlled double-blind studies with larger samples should be undertaken to evaluate the effects of alprazolam in a range of child psychiatry disorders. Assessor’s Comment In this trial although alprazolam treatment was associated with significant clinical global and symptomatic improvement, the study design (open label) and the very small number of patients (n=10) reduce the robustness of these findings. Furthermore the self-rating scale of anxiety and
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the children’s psychiatric self rating showed no changes. Regarding the safety of the treatment, no unexpected adverse events were reported in this study. As in the study by Ferguson et al (see comments below), there was no deterioration of the cognitive functions during the alprazolam treatment. Ferguson HB, Simeon JG. Evaluating drug effects on children's cognitive functioning. Progr NeuroPsychopharmacol Biol Psychiatry 1984;8(4-6):683-6. Twelve children with overanxious disorders were treated in an open trial with alprazolam. Cognitive tests were administered at the end of baseline placebo (1 week), alprazolam therapy (4 weeks), and post-drug placebo (2 weeks) periods. Both child and tester were blind to the medication condition. Paired T-tests were used to test for a drug effect (baseline placebo vs. medication) and for relapse (medication vs. post-drug placebo). The only significant differences reflected improved performance from baseline placebo to medication conditions on paired-associate learning, mazes, and block design. The authors concluded that alprazolam at therapeutically effective doses had no adverse effects on cognition and learning. Assessor’s Comment Ferguson et al report the effect of the treatment with alprazolam in 12 children with overanxious disorders in an open trial using cognitive tests at the end of baseline placebo (1 week), alprazolam therapy (4 weeks), and post-drug placebo (2 weeks) periods. The authors concluded that although no positive effects were expected, it is encouraging that no evidence of deterioration of cognitive performance was found. 4. Overview of safety No deaths were reported in any of the MAH sponsored studies submitted under this European paediatric work-sharing procedure. No serious adverse events were reported in trials A6131002, A6131003 and A6131007. The following 3 serious events were reported in trial A6131004: (1) therapeutic agent toxicity (investigator term: benzodiazepine intoxication), anxiety disorder, depression, and disinhibition following a dose of alprazolam XR 12 mg/day (2) overdose, recovered the same day, (3) factitious disorder. Discontinuation due to adverse events occurred in 8/45 subjects in study A6131004, 3/15 in A6131002 and none in A6131003 and A6131007. The observed adverse event profile appeared to be similar that that in adults. From the review of the evidence in the 7 published articles submitted by the MAH, treatment with alprazolam appeared to be well tolerated and there were no new safety concerns identified in those trials. An encouraging fact is the cognitive performance doesn’t appear to be affected in children treated with alprazolam for anxiety disorders although evidence was generated in small scale open label studies. In addition, a review of the MAH’s Postmarketing Safety Database was performed. The MAH’s safety database contains cases of adverse events reported spontaneously, cases reported by health authorities, cases published in the medical literature, and cases of serious adverse events reported from clinical studies and MAH-sponsored marketing programs regardless of causality. The database was searched for all medically confirmed cases where alprazolam was specifically prescribed to paediatric patients (where age was reported as ≤17 years, or the patient was described as a newborn, neonate, infant, child, adolescent, or teenager by the reporter) and that were reported from the international birth date (12 March 1980) through 31 December 2010. A total of 55 cases (139 adverse events) were identified. When reported, patients ranged in age from 4 through 17.0 years, with a mean age of 13.9 years. The most common adverse events reported were Nervous system disorders (37), Psychiatric disorders (26) General disorders and
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administration site conditions (20), Injury, poisoning, and procedural complications (14), and Investigations (10). The MAH concluded that “Due to the small number of cases reported in the paediatric population, a meaningful comparison between the adverse events in pediatric versus non-pediatric patients could not be made.” The adverse events reported in ≥2% of the medically confirmed alprazolam paediatric cases are presented in Table 4. Table 4: Summary of Adverse Events Reported in ≥2% of Medically Confirmed Paediatric Cases
The MAH also reviewed that Alprazolam safety update reports (PSURs) from three periods that covered the dates from 10 January 1997 through 11 March 2010 and provided a summary of the paediatric safety findings from these reports. In the first report, covering the period 10 January 1997-31 January 2002, no new significant safety information was identified upon review of cases involving the paediatric population. During period 2 (01 February 2002 through 31 March 2007), there were 45 cases (including 133 events) involving children representing 2.6% of all cases. Within this dataset, there were 21 females, 8 males and 6 cases of unknown gender. Outcomes in these 45 cases included recovered or recovering in 18 cases, not recovered in four cases, and in 10 cases the outcome was not known at the time of the report. Thirteen of these cases reported death as the outcome. These cases involved multiple drug overdoses with alprazolam and or other medications as the agents of suicide or overdose with unknown intent. Most of these cases originated from literature reports and only provided a minimum of information. The greatest number of cases in the
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paediatric population included Injury, poisoning and procedural complications (20), Nervous system disorders (16), General disorders and administration conditions (10) and Psychiatric disorders (10). The most commonly reported adverse events irrespective of the SOC were Cardiac arrest (8), Respiratory arrest (8), Accidental exposure (7), Somnolence (7) and Drug abuser (6). During period 3 (01 April 2007 through 11 March 2010), there were 51 cases (involving 131 events) involving children representing 3.7% of all cases. Among this dataset, there were 25 females, 19 males and 7 patients of unknown gender. Case outcome was reported as recovered in 15 cases, recovered with sequelae in 1 case, unknown in 18 cases and fatal in 17 cases. Among these 17 fatal cases, 9 cases were from literature articles published in Clinical Toxicology. In 2 of these 9 cases, patients committed suicide with multiple drug ingestion and died of cardiac and respiratory arrest. In five other cases, the patients died of abuse/misuse of multiple medications, including alprazolam. One case that provided limited information described a 1-day-old male who died due to malicious harm. Another case involved a 3-year-old male who died of an unintentional therapeutic error after an acute exposure to parenteral phenytoin and alprazolam. One other case from the literature that provided limited information involved a 15-year-old male who died of poisoning with alprazolam and buprenorphine. In the remaining 7 spontaneous cases, the patients died due to multiple drug ingestions or overdose with multiple drugs. In these cases, the amount of alprazolam ingested, indication, daily dose, and duration of therapy, were not reported. During the same period, the greatest number of events in the paediatric population included Injury, poisoning and procedural complications (28 events), Psychiatric disorders (25), and Nervous system disorders (23). The most commonly reported adverse events irrespective of SOC were Accidental drug intake by child (7 events), Cardiac arrest (7), Respiratory arrest (7), Somnolence (6), Drug abuse, and Intentional drug misuse (5 events each).
Assessor’s Comment The safety data provided by the MAH for this European work-sharing procedure under Article 45 are very limited as these have been previously reviewed in regularly submitted PSURs. It is noted that the most recent PSUR contained 51 cases (131 events), i.e. an additional 4 cases and 8 events were identified in the MAH’s Postmarketing Safety Database review and the MAH is asked to provide further details for these additional cases. Overall the available information suggests that the adverse events experienced by children exposed to alprazolam are similar to those experienced by the adult population. However, the total experience remains very small to allow a meaningful comparison between the adverse events in paediatric versus non-paediatric patients. It is noted that from the PSUR data, a significant proportion of the alprazolam cases in paediatric patients involved ingestion of alprazolam with other drugs, sometimes in overdose, intentional or due to medication error. 5. Discussion on clinical aspects From the data provided by the MAH in this European work-sharing procedure under Article 45, there is no robust evidence supporting the use of Alprazolam in paediatric patients. The currently available data from MAH-sponsored clinical trials and published medical literature remain inconclusive. No large scale, placebo controlled clinical studies have been conducted by the MAH to support the safety and efficacy of alprazolam use in paediatric patients ≤17 years of age. The majority of the MAH-sponsored studies of alprazolam XR in adolescents were terminated early due to recruitment difficulties. Therefore, given that only five patients completed any of these early terminated trials no efficacy conclusions can be drawn from these data. Data derived from the published literature did demonstrate likely efficacy and safety in a few of the studies reviewed; however, most of the studies were not well controlled and the paediatric sample size of patients across studies was relatively small.
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In study A6131003 the MAH presents the similarities found in the PK parameters after a single dose of alprazolam of healthy adolescents and young adults. The rapporteur is of the view that as the balance of risks and benefits in the paediatric population has not been established, the inclusion of the PK findings in section 5.2 “Pharmacokinetic properties” could be potentiating misleading for the prescribers. The review of the currently available paediatric data from MAH-sponsored studies, published literature, and post-marketing surveillance data did not reveal any new safety concerns in the paediatric population. The adverse events observed in a rather limited sample of adolescent subjects were considered to be similar to those observed in adult trials of alprazolam. The significant number of overdoses among adolescents is of concern but the rapporteur is of the view that this large reflects the use of benzodiazepines with other drugs in intentional overdosing among this population. The MAH concluded that no change to the draft alprazolam Core Safety Profile, which is currently under review, is warranted at this time. The current statement included in the draft alprazolam Core Safety Profile is as follows: Safety and efficacy of alprazolam have not been established in children and adolescents below the age of 18 years; therefore use of alprazolam is not recommended.
III. RAPPORTEUR’S CONCLUSION AND RECOMMENDATION AT DAY 89
The presented data submitted in this article 45 European work-sharing procedure is insufficient to support a variation regarding the use of Alprazolam in the paediatric population. The rapporteur supports the inclusion of the following statement in the SmPC in all Alprazolam containing products across the EU should include the following statement: 4.2 Posology and method of administration Paediatric patients: Safety and efficacy of alprazolam have not been established in children and adolescents below the age of 18 years; therefore use of alprazolam is not recommended. Following the circulation of the preliminary Day 70 report, we received comments from 5 MSs who fully supported the rapporteur’s overall confusion and recommendation and had no further comments. However additional clarifications were requested. The MAH was requested to provide information regarding the additional cases included in the review of the MAH’s postmarketing safety database which have not previously included in the last PSUR. Furthermore the MAH was requested to propose the paediatric wording which should be included in the PIL of all alprazolam containing preparations reflecting the available paediatric information.
IV. MAH RESPONSE TO THE PRELIMINARY PDAR In October 2011, the MAH sent a response agreeing with comments and conclusions of the rapporteur and provided the requested information. Regarding the additional cases included in the review of the MAH’s postmarketing safety database, the MAH sent the following response: “In response to the request from the EMA/CMDh, the MAH’s’s safety database was searched for all medically confirmed cases where alprazolam was intentionally prescribed to pediatric patients that were reported from the international birth date (12 March 1980) through 31 December 2010. As conducted, this search identified 55 cases during an approximately 30 year period. The
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majority of these cases (47) were either reported during a previous PSUR reporting period or prior to the preparation of the first alprazolam PSUR. The remaining eight cases were received with the integration of other company databases, did not meet PSUR inclusion criteria, or were received after the datalock point of the most recent PSUR.” A narrative line listing of the paediatric treatment cases that have not previously reported (29 cases) was presented as an appendix in the MAH’s response document. Assessor’s Comment The MAH provided a narrative line-listing of Alprazolam paediatric treatment cases not reported in a previous PSUR. In the majority of the cases, the patients’ age was older than 11 years although one case of a 4 year old child who received 0.5mg Alprazolam as sedation for an MRI of the head and developed fever (case resolved). There was also a case of stillbirth in a 14 year old mother who had taken Alprazolam for approximately 2 weeks at 1st and 2nd trimester. Three fatal cases after drug overdosing were identified which involved patients older than 15 years; in all cases a significant number of different drugs were taken simultaneously. In the remaining cases no new safety concerns or unexpected ADRs have been identified from this report. The MAH was also requested to propose the paediatric wording which should be included in the PIL of all alprazolam containing preparations reflecting the available paediatric information. The applicant suggested the following wording to be included in section 2 of PIL: Section 2 “What you need to know before you take <alprazolam>” Children and adolescents <alprazolam> is not recommended for children and adolescents under the age of 18 years. Assessor’s Comment The proposed wording for the PIL of all alprazolam containing products is accepted.
V. MEMBER STATES OVERALL CONCLUSION AND DRAFT
RECOMMENDATION Based on the review of the presented paediatric data the rapporteur considers that for all products containing alprazolam across the EU, it is recommended that SmPCs and PILs contain the following statements: SmPC wording 4.2 Posology and method of administration Paediatric patients: Safety and efficacy of alprazolam have not been established in children and adolescents below the age of 18 years; therefore use of alprazolam is not recommended. PIL wording Section 2 “What you need to know before you take alprazolam” Children and adolescents Alprazolam is not recommended for children and adolescents under the age of 18 years. The applicant is therefore requested to submit a Type IB variation to update the SmPCs and PILs of products containing alprazolam in line with the above work-sharing recommendations.
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ANNEX I PROPOSED WORDING AND NL TRANSLATION SmPC tekst 4.2 Dosering en wijze van toediening Pediatrische patiënten
De veiligheid en werkzaamheid van alprazolam is niet vastgesteld bij kinderen en adolescenten onder 18 jaar; het gebruik van alprazolam wordt daarom niet aanbevolen.
Bijsluiter tekst 2. Wanneer mag u dit middel niet <gebruiken><innemen> of moet u er extra voorzichtig mee
zijn? Kinderen en jongeren tot 18 jaar Alprazolam wordt niet aanbevolen voor kinderen en adolescenten onder 18 jaar.
