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Clinical Pharmacology Review
PRODUCT (Generic Name): Esomeprazole Magnesium
PRODUCT (Brand Name): Nexium
DOSAGE FORM: Delayed-Release Granules for Oral Suspension
DOSAGE STRENGTH: 10 mg (in a packet)
NDA: 22-
PROPOSED INDICATIONS: Short-term Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD) and Healing of Erosive Esophagitis (EE) once daily for 8 Weeks
TARGET POPULAITON: Pediatric Patients 1-11 Years Old
NDA TYPE: Original
SUBMISSION DATE: September 27, 2006, December 06, 2006, and May16, 2007
SPONSOR: AstraZeneca LP
REVIEWER: Tien-Mien Chen, Ph.D.
TEAM LEADER: Sue-Chih Lee, Ph.D.
OCP DIVISION: DCP III
OND DIVISION: Division of Gastroenterology Products (HFD-180)
1. Executive Summary
Esomeprazole magnesium (hereafter referred to as esomeprazole) is the pure S-enantiomer of the racemic omeprazole. It is a proton pump inhibitor (PPI) that suppresses gastric acid secretion by specific inhibition of the H/K + -ATPase in the gastric parietal cell. The first oral Nexium (esomeprazole) formulation on the market was the delayed-release (DR) capsules (20 and 40 mg) approved for adult patients on 02/20/ under NDA 21-153 for the treatment of GERD (gastroesophageal reflux disease) and gastric-acid related gastrointestinal (GI) disorders.
Pediatric written request (PWR) for Nexium was issued by the Agency initially on 12/31/01 with subsequent revisions. The PWR requires that the sponsor conduct studies in pediatric patients of all ages (neonates and preterm infants, 1-11 months, 1-11 yrs, and 12-17 yrs). Nexium DR capsules (20 and 40 mg) were approved for adolescent patients 12-17 years old under NDA 21-153/S-022 on 04/28/06.
The second oral Nexium formulation approved by the Agency was DR granules for oral suspension (20 and 40 mg) which was approved for use in patients 12 years of age and older under NDA 21-957 on 10/20/06. The approval was based on bioequivalence (BE) assessment in an in vivo pharmacokinetic (PK) study comparing it with the approved DR capsules without clinical trials. The study results showed that the formulation of DR granules for oral suspension was BE to DR capsule formulation.
In this NDA, the sponsor is pursuing the approval of a lower strength (10 mg) of Nexium DR granules for oral suspension for use in pediatric patients 1-11 years of age. Four studies were provided in the NDA: 1) a multiple-dose, Phase-1 PK study in pediatric patients 1-11 years old (D9614C00099), 2) a multicenter randomized double-blind parallel-group dose-response trial in pediatric patients 1-11 years old (D9614C00097), 3) an in vivo PK study for assessing the BE between Nexium DR granules for oral suspension and DR capsules in healthy adult subjects (D9612C00032), and 4) a supportive pediatric study in patients aged 1-24 months (SH-NEC-001).
The in vivo BE study (D9612C00032) had been reviewed under NDA 21-957 and the Phase III dose-response trial (D9614C00097) is being reviewed by the medical officer of HFD-180. Therefore, this review covers the multiple-dose PK study in patients 1- years old (D9614C00099) and the supportive PK, pH-monitoring, and safety study in patients aged 1-24 months (SH-NEC-0001).
A. Recommendation:
NDA 22-101 for Nexium DR granules for oral suspension 10 mg has been reviewed by Office of Clinical Pharmacology/Division of Clinical Pharmacology III (OCP/DCP III). The NDA is found acceptable from OCP perspective provided that a mutually satisfactory agreement regarding the package insert can be reached between the sponsor and the Agency. The labeling comments (p. 17) should be conveyed to the sponsor.
B. Comments
- Regarding the sponsor’s proposed dosing regimens for patients aged 1-11 years:
The proposed dosing regimens of 10 mg QD (for all patients in the specified age range) and 20 mg QD (for healing of erosive esophagitis in patients weighing ≥ 20 kg) are reasonable based on the PK findings from Study D9614C00099. The appropriateness of the above proposed dosing regimens based on the dose-response trial is being evaluated by the Medical Officer of HFD-180.
II. Table of Contents
Page I. Executive Summary ……………………………………………………………. 1 II. Table of Contents ………………………………………………………………. 4 III. Summary of CPB Findings ……………………………………………………. 4 IV. QBR ………………………………………………………………..…………… 7
V. Detailed Labeling Recommendations………………………………………. 17
VI. Appendices …………………………………………………………………... 19
III. Summary of Clinical Pharmacology Findings
This review covers the multiple-dose Phase I PK study in patients aged 1-11 years (D9614C00099) and the supportive PK, pH-monitoring, safety study in infants aged 1- months (SH-NEC-001). The dose-response trial (D9614C00097) is being reviewed by the Medical Officer of HFD-180.
Multiple-dose PK Study (D9614C00099): In this study, Nexium DR granules for oral suspension was administered once daily to patients aged 1-11 years with GERD or symptoms of GERD for 5 days. The 5 and 10 mg doses were chosen for patients aged 1-5 years and 10 and 20 mg doses for patients aged 6-11 years. The PK parameters on Day 5 are shown in the table below:
Summary of PK Parameters in Pediatric Patients 1-11 Years Old
For children aged 1-5 years, the AUC, AUC (^) (0-t), and C (^) max were 5- to 7-fold higher for the 10 mg dose group compared to the 5 mg dose group. The reason for this observation is unknown. The sponsor is not pursuing the 5 mg dose in this NDA For children aged
6-11 years, these parameters were approximately twice as high for the 20 mg dose group compared to the 10 mg dose group. Mean body weight (BW) normalized apparent clearance (CL/F/kg) was slightly higher in children aged 1-5 years who received the 10-mg dose than in those aged 6 to 11 years who received either the 10-mg or 20-mg dose. However, high intersubject variability (%CV: 44-84%) was observed in all age and dose groups.
Comparison of Systemic Exposure Among Different Age/Dose groups: The systemic exposure observed in this study is compared to historical data in adults and adolescents (see Table below). The findings are:
- 5 mg dose/1-5 year olds: Mean AUC (0.74 μmol.h/L) was much lower than that for any other dose/age groups shown in the table below. The reason for this observation is unknown. As such, the efficacy of the 5 mg dose in patients aged 1-5 years is uncertain in view of the PK findings.
- 10 mg dose/1-5 year olds: Mean AUC (4.8 μmol.h/L) was similar to that observed for the 20 mg dose in adults (4.2 μmol.h/L). It was in between those for the 10 mg dose in the 6-11 year olds (3.7 μmol.h/L) and 20 mg dose in the 6-11 year olds (6.3 μmol.h/L).
- 10 mg dose/6-11 year olds: Mean AUC (3.7 μmol.h/L) was the same as that for the 20 mg dose in adolescents (3.7 μmol.h/L).
- 20 mg dose/6-11 year olds: Mean AUC (6.3 μmol.h/L) was higher than that observed for the 20 mg dose given to adolescents (3.7 μmol.h/L) or adults (4.2 μmol.h/L), but much lower than that observed with the 40 mg dose given to adolescents (13.9 μmol.h/L) or adults (12.6 μmol.h/L). As such, none of the pediatric doses tested in this study showed their plasma AUC values close to those observed with the 40 mg dose in adults and adolescents.
- Based on the above findings, the proposed dosing regimens of 10 mg QD (for all patients aged 1-11 years) and 20 mg QD (for healing of erosive esophagitis in patients weighing ≥ 20 kg) is reasonable.
Comparisons of Esomeprazole Dose and Systemic Exposure Among
Different Age groups
IV. Question Based Review
A. General Attributes
Drug Substance: Esomeprazole magnesium (hereafter referred to as esomeprazole) is the pure S-enantiomer of the racemic omeprazole. It is also the drug substance used for the approved DR capsules (20 and 40 mg).
Formulation: For Nexium DR granules for oral suspension, esomeprazole is manufactured as pellets and is identical to that for the approved DR capsules. The contents of DR granules for oral suspension in packet contain esomeprazole pellets and excipient granules (please see Table 6 on p. 16 of this review). The 20 and 40 mg strengths were approved by the Agency on 10/20/06 for use in patients aged 12 years and older (NDA 21-957).
The composition/formulation for the 10 mg strength is the same as that for the approved 20 and 40 mg strengths. The different product strengths are obtained by filling varying amounts of esomeprazole pellets and excipient granules into the packet. The exact amount of esomeprazole pellets in the packet is based on the content of the active drug in the pellets.
Mechanism of Action: Esomeprazole is a PPI that suppresses gastric acid secretion by specific inhibition of the H+ /K+ -ATPase in the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity and leading to inhibition of gastric acid secretion.
B. General Clinical Pharmacology
Proposed Indication and Dosing Regimen: For pediatric patient 1-11 years old, the proposed indication and dosing regimen are shown below:
Recommended Dosage Schedules of Nexium
Indication Dose Frequency For pediatric Use (1-11 Years Old):
Short-term treatment of 10 mg Once Daily for up to 8 weeks symptoms of GERD
Healing of Erosive Esophagitis
Weight <20 kg 10 mg Once Daily for 8 weeks Weight ≥20 kg 10 mg or Once Daily for 8 weeks 20 mg
The contents of the packet are to be mixed with water and the suspension can be left for up to 30 minutes before administration.
Pediatric Studies in patients aged 1-11 years as listed in the PWR: The pathophysiology of GERD in children older than 1 year of age is considered to be similar to that in adults. As in adults, the acidic nature of the refluxate and the presence of activated pepsin are considered to be the principal irritants causing mucosal inflammation, resulting symptomatology, and other potential long-term outcomes associated with GERD. It is generally accepted that the clinical course and manifestation of GERD in the 1 to 17 year old pediatric population is similar to that of adult populations.
The PWR for Nexium was first issued by the Agency initially on 12/31/01 with subsequent amendments. The first group studied in the Nexium pediatric program consisted of adolescent patients aged 12 to 17 years old, inclusive (Study 5 in PWR). Data on the usage of the approved DR 20 and 40 mg capsules for this age group was approved by the Agency under NDA 21-153/S-022 on 04/28/06.
The second age group studied in the Nexium pediatric clinical program consisted of pediatric patients 1 to 11 years old, inclusive, the subject of this NDA submission. It is designed to support the used on Nexium DR granules (in packet) for oral suspension in pediatric patients 1-11 years old as indicated in the PWR (Study 4). In addition, a supportive pediatric study was also submitted to assess the PK of esomeprazole and its efficacy in controlling intragastric pH in pediatric patients 12-24 months.
The study in patients aged 1-11 years as delineated in the PWR (revised as of 03/29/07) is shown below:
Q1. How were the doses selected for the pediatric studies?
Based on work done with previously available omeprazole and esomeprazole data using appropriate modeling techniques and a thorough review of pediatric PK and PD literature, the esomeprazole exposure (AUC) and the response (efficacy and safety) relationship in a pediatric population were established via a comprehensive PK and population PK modeling analysis of the omeprazole data in pediatric and adult patients and the esomeprazole data in adult patients.
Assuming 7 to 60 kg of body weight for children 1-11 years old, the proposed 5 mg dose would have a reasonable chance to show efficacy and acceptable safety for children weighing 7 to 25 kg, the 10 mg dose for children weighing 7 to 60 kg, and the 20 mg dose for children weighing 12 to 60 kg (children between the ages of 1 and 5 years old, inclusive have a typical body weight between 7 and 20 kg and 6-11 years old between 20 and 60 k.). Thus, 5 and 10 mg doses were selected for pediatric patients 1-5 years old (or BW <20 kg) and 10 and 20 mg doses were for pediatric patients 6-11 years old (or BW ≥ 20 kg). The doses selected for PK (based on age) and Phase III trials are consistent (based on BW) as shown below:
Dose Selected PK Study Phase III Trial 5 and 10 mg 1-5 years old BW < 20 kg 10 and 20 mg 6-11 years old (^) BW ≥ 20 kg
Q2. What are the pharmacokinetic characteristics of esomeprazole
in pediatric patients aged 1-11 years?
A PK study (No. D9614C00099) entitled “A Randomized, Open-Label Study to Evaluate the Pharmacokinetics of Multiple Doses of Esomeprazole Magnesium in a Pediatric Population of 1 to 11 Year olds with Gastroesophageal Reflux Disease (GERD) or Symptoms of GERD” was conducted. The study design and results are shown below in Scheme 1 and Table 1, respectively:
Scheme 1. Study Design
Table 1. Summary of PK Parameters in Pediatric Patients 1-11 Years
Old
The AUC, AUC (^) (0-t), and C (^) max were several-fold lower for 5 mg esomeprazole compared with 10 mg esomeprazole in children aged 1 to 5 years, while the same parameters were approximately 2 times lower for 10 mg esomeprazole compared with 20 mg esomeprazole in children aged 6 to 11 years. One factor that may have contributed to this difference may be the higher weight for 5 mg treatment group (21.0 ± 5.8 kg) vs. 10 mg treatment group (14.7 ± 3.3 kg) and thus lower actual (mg/kg) esomeprazole doses in children receiving the 5 mg dose. The above weight difference could only explain partially the 5- to 7-fold difference in PK parameters. However, the exact reason for this is not known.
Q3. How Do PK Parameters in Pediatric Patients Aged 1-11 Years
Compare with Those in Adolescent and Adult Patients? Are
the Proposed Dosing Regimens for Patients Aged 1-11 Years
Reasonable Based on the PK Findings?
The PK parameters obtained from this study in 1 to 11 year old children were compared with those from adolescent 12 to 17 year old and from adult studies as shown below:
Figure 1. Cumulative Percentage of Patients and Number of Days to
First Sustained Resolution of the Combined GERD
Symptoms Heartburn, Acid Regurgitation, and Epigastric
Pain—ITT population
Improvement in EE: Patients were considered to be improved if they were better than they were at baseline. Patients were resolved if their final endoscopy showed no signs of erosions. Analysis of the follow-up endoscopies of patients in Phase III trial who had EE at baseline by endoscopy showed that EE was improved or healed in the majority of patients after 8 weeks of esomeprazole treatment. Overall, 93.3% (42) of the 45 patients who had EE at baseline and had a follow-up endoscopy showed improvement in their final endoscopy results. In most of these patients (88.9%, 40/45), the EE was resolved and their erosions had healed. Eleven patients (1-5 years old in the 5 mg treatment group) who had EE, however, were all reported healed as shown below in Table 3. No clear dose-response was observed with this outcome measure. Again, no control/comparator group was employed in this study.
Table 3. Summary of Clinical Outcome for Patient who had EE at
Baseline and had Follow-up Endoscopy –ITT Population
Note : For safety assessment, it is reported that the adverse event (AE) profile of esomeprazole in pediatric patients aged 1 to 11 years did not raise any new safety concerns. In general, the AEs reported were consistent with the known safety profile of esomeprazole. No new safety signals were identified in this population of 1 to 11 year old pediatric patients and AE occurrences did not appear to be dose related.
Q5. What information from Study No.SH-NEC-0001 can be used to
support the proposed dosing regimens in Patients Aged 1-
years?
The supportive study No. SH-NEC-0001 was conducted in 50 pediatric patients 1- months employing repeated dose of 0.25 mg/kg (n=26) or 1.0 mg/kg (n=24) for 7-8 days. PK and intragastric and intraesophageal pH values were obtained. The study results provided some evidence of positive trend of dose vs. mean change in % of time with intragastric pH> 4 and with intraesophageal pH <4 as shown below in Tables 4 (1- months; n=22) and 5 (only for 12-24 months; n=6). Because of the small sample size of patients aged 12-24 months (n=6), the data from this study are not deemed useful.
**Table 4. Mean Percentage of Time with Intragastric pH>4 and Intraesophageal pH<4 at Baseline and After One Week of Treatment (Day 7/8) for Patient. 1-24 Months Pharmacodynamic Parameters 0.25 mg/kg 1.0 mg/kg Baseline Day 7/8 Change Baseline Day 7/8 Change % of Time with Intragastric pH
4 in 24 hr**
(n=22)
(n=22)
(n=21)
(n=22)
(n=22)
40.6; (26.6)^2
(n=21) p value -----^ -----^ -----^ -----^ 0.0009^1 <0.0001^3 % of Time with 11.6 8.4 -3.5 12.5 5.5 -6.7; (-3.3)^2 Intraesophageal pH <4 in 24 hr (n=23) (n=23) (n=23) (n=22) (n=22) (n=21) p value ----- ----- ----- ----- 0.171 1 0.0615 3 (^1). Comparison on Day 7/8 between two dose levels (and significant if p<0.05). (^2). Comparison of change/improvement on Day 7/8 from baseline between two dose levels. (^3). Significantly different if p<0.05.
lation of esomeprazole granules (in packet) for oral suspension 10 5 mg tested clinically are compositionally the same and s the approved 20 and 40 mg granules (NDA 21-957) as shown
ition/Formulation of Esomeprazole Granules in Packet for Oral Suspens ion
C. Intrinsic Factors:
It appears that esomeparazole PK in adolescents are similar to those in adults. However, PK in younger children (<12 years) appear to be different from those aged 12 years and above as suggested by the following:
Comparison of AUC between the age groups of 6-11 years and 12-17 years:
- AUC was similar between the 10 mg dose in the 6-11 yr olds (mean dose: 0.34 mg/kg) and 20 mg dose in the 12-17 yrs olds (mean dose: 0.32 mg/kg). However, AUC for the 20 mg dose in the 6-11 yr olds (mean dose: 0.71 mg/kg) was less than half of that for the 40 mg dose in the 12-17 yrs olds (mean dose: 0.64 mg/kg).
D. Extrinsic Factors: N/A
E. General Biopharmaceutics:
The composition/formu mg plus the 2.5 and proportionally similar a below in Table 6.
Table 6. The Compos
The initial esomeprazole DR pellets in granule formulation was developed in capsule form and used in the earlier supportive study No. SH-NEC-0001. The contents of capsules were dispersed on applesauce or emptied into a funnel pan and administered through a specially designed adapter (>1 to <3 months of age). The capsule dosage form was also used in pediatric patients in the other two studies, Nos. D9614C00099 and
D9614C00097 and for those who could not swallow intact capsules, contents sprinkled on applesauce were used. Because the granules containing the active ingredient in the proposed formulation are identical to granules in the DR capsules and the in vitro comparative dissolution data were comparable as reviewed previously under NDA 21-957, no differences in PK performance between DR granules and DR capsules are expected.
F. Analytical Section
For study No. D9614C00099, plasma samples for determination of esomeprazole were analyzed at DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Sweden using validated liquid chromatography and LC/MS/MS according to method No. BA-410-01, “Analytical Method for Determination of Esomeprazole or Omeprazole, in Human Heparin Plasma by LC-MS/MS”, (AstraZeneca R&D Mölndal Analytical Method No. BA-410-01, 7 September 2004). The nominal concentrations of esomeprazole performed ranged from 20-20000 nmol/L with the limit of quantification (LOQ) of 20 nmol/L for esomeprazole. The quality control (QC) samples, 59.1 (n=12), 626 (n=12), and 16000 nmol/L (n=12), showed precision with coefficient of variation (CV%) of 2.1-4.8% and an overall mean of accuracy of 98.9 – 105.9%.
The following CP labeling recommendations should be conveyed to the sponsor; sponsor’s addition (double underlined), Agency’s addition (blue and underline), and deletion (red and double strkethrough)
V. Detailed Labeling Recommendations
For study No, SH-NEC-0001, the same method was used. The nominal concentrations of esomeprazole performed ranged from 5-5000 nmol/L with the limit of quantification (LOQ) of 5 nmol/L for esomeprazole. The quality control (QC) samples, 44.7-54. (n=14), and 960-1100 nmol/L (n=14), showed precision with coefficient of variation (CV%) of 1.6-4.8% and an overall mean of accuracy of 99.6 – 107.1%. assay methods were reviewed and found acceptable.
The above two
VI. Appendices
1. Proposed Package Insert (Original and Annotated)
2. Individual Study Review
3. Cover Sheet and OCPB Filing/Review Form
NDA 22-101 for Nexium (Esomeprazole Magnesium) Granules in Packet for Oral Suspension
Appendix 1
Sponsor’s Proposed PI (Annotated; 01/17/2007 version)
