CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`022063Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
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`
`
`
`

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`Office of Clinical Pharmacology Review
`
`NDA
`Link to EDR
`Submission Date
`Submission Class
`Brand Name
`Generic Name
`Dosage Form and Strength
`
`Route of Administration
`Proposed Indication
`
` Applicant
`Related IND
`OCP Review Team
`
`OCP Final Signatory
`
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`
`
`022063
`\\CDSESUB1\evsprod\NDA022063\0022
`12/20/2016
`Priority (Class 2 Resubmission)
`Mydayis®
`Mixed salts of a single entity amphetamine
`Extended Release Capsule 12.5 mg, 25 mg,
`37.5 mg and 50 mg
`Oral
`Attention Deficit Hyperactivity Disorder
`(ADHD)
`Shire
`66,329
`Kofi A. Kumi, Ph.D., Michael Bewernitz,
`Ph.D., Kevin Krudys, Ph.D., Hao Zhu, Ph.D.
` Mehul Mehta, Ph.D.
`
`Table of Contents
`1. Executive Summary ............................................................................................................................ 3
`1.1 Recommendations ............................................................................................................................... 3
`1.2 Post-Marketing Requirements and Commitments ............................................................................... 5
`2. Summary of Clinical Pharmacology Assessment ...................................................................................... 5
`2.1 Pharmacology and Clinical Pharmacokinetics .................................................................................. 5
`2.2 Dosing and Therapeutic Individualization ......................................................................................... 8
`2.2.1 General Dosing ............................................................................................................................ 8
`2.3 Outstanding Issues .............................................................................................................................. 9
`2.4 Summary of Labeling Recommendations .......................................................................................... 10
`3. Comprehensive Clinical Pharmacology Review ............................................................................. 10
`3.1
`Overview of the Product and Regulatory Background ............................................................. 10
`3.2 General Pharmacological and Pharmacokinetic Characteristics .................................................... 12
`3.3 Clinical Pharmacology Questions ..................................................................................................... 13
`3.3.1 To what extend does the available clinical pharmacology information provide pivotal or
`supportive evidence of effectiveness? ................................................................................................. 13
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`Reference ID: 4109794
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`3.3.2 Is the proposed general dosing regimen appropriate? .............................................................. 13
`3.3.3 Is an alternative dosing regimen and management strategy required for subpopulations based
`on intrinsic factors? ............................................................................................................................ 16
`3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate
`management strategy? ........................................................................................................................ 17
`3.3.5 Are the Exposures to d- and l- amphetamine after SHP465 and Adderall XR + Adderall IR
`similar? ............................................................................................................................................... 20
`3.3.6 What are the Pharmacokinetic characteristics of d- and l- amphetamine after administration of
`SHP465 to pediatric patients 6 – 12 and 13 -17 years old and how do they compare to Adults? ...... 22
`4. Appendices .......................................................................................................................................... 26
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`Reference ID: 4109794
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`1. Executive Summary
`
`This NDA is a Class 2 Resubmission for a triple-bead amphetamine extended release product
`(SHP465) by Shire Pharmaceuticals. It is a complete response to an approvable letter that was
`issued for NDA 22063 in May 2007. Even though the sponsor notified the Agency in May of
`2007 of intent to file an amendment to support approval, they decided not to pursue the
`development of SHP465 at that time for business reasons. The sponsor has reactivated the
`development program for SHP465 and is currently seeking approval for SHP465 under the
`tradename of Mydayis® for the treatment of Attention Deficit Hyperactivity Disorder (ADI-ID).
`
`SHP465 is a once—daily, triple-bead, sustained-release, single-entity mixed amphetamine salt
`(MAS) product for oral administration.
`(m4)
`
`Adderall XR which is manufactured by the same Sponsor and approved for ADHD. m“)
`
`This triple—bead, sustained—release delivery is intended to extend the release of the MAS from
`SHP465 for symptom coverage up to 16 hours post—administration. Adderall XR reportedly lasts
`about 12 hours. The need for a longer duration of symptom coverage was justified by multiple
`reports that, in clinical practice, Adderall XR is supplemented afier 8 hours with MAS immediate
`release (1R) to extend the duration of action to last during waking hours.
`
`The clinical development program consisted of 16 clinical studies, 13 of which were included in
`the original NDA, and 3 of which (i.e., one PK trial in pediatric patients aged 6—17 years, one
`eflicacy and safety trial in pediatric patients aged 6-17 years, and one efficacy and safety trial in
`adults aged 18—55 years) are new and included in this resubmission. A population
`pharmacokinetic analysis report was also included in this resubmission.
`
`The key review issues are: 1) is the exposure after administration of SHP465 similar to the
`reference drug, Adderall XR plus the administration of MAS IR after 8 hours? 2) Is the proposed
`dosing regimen appropriate? 3) Should SHP465 to be administered with or without food? 4) Are
`there dose adjustments in renal impairment patients or patients receiving a gastric pH modulator?
`
`1.1 Recommendations
`
`The Office of Clinical Pharmacology (OCP) has reviewed the information contained in NDA
`
`022063 and supports the approval of the SHP465 for the treatment of Attention Deficit
`
`Hyperactivity Disorder. OCP supports limiting the use of SHP465 to patients 13 years and older.
`
`Key review issues with specific recommendations and comments are summarized below:
`
`Review Issues
`
`Recommendations and Comments
`
`Overall. the proposed dosing is acceptable in adults and pediatric
`
`Supportive evidence of effectiveness
`
`General Dosing Instructions
`
`demonstrated in
`effectiveness was
`evidence of
`Substantial
`registration trials in adults and pediatric patients. The uniqueness of
`this formulation is that the duration of action after administration of
`
`SHP465 is about 16 hours compared to about 12 hours for currently
`approved mixed amphetamine salts extended release formulations.
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`Reference ID: 41 09794
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` The proposed doses are not
`patients 13 years and older.
`recommended for pediatric patients 6 to 12 years of age.
`
`
`The recommended starting dose in adults 18 to 55 years is 12.5 mg
`once daily in the morning upon awakening. Dosage may be adjusted
`in increments of 12.5 mg no sooner than weekly to a maximum dose
`of 50 mg/day.
`The recommended starting dose in pediatric patients 13 to 17 years
`old is 12.5 mg daily in the morning upon awakening. Dosage may be
`adjusted in increments of 12.5 mg no sooner than weekly to a
`maximum dose of 25 mg/day
`
`Doses may be taken with or without food. However, in order to
`ensure consistent clinical response, patients should endeavor to take
`SHP465 either with food always or without food consistently.
`The whole content of a capsule may be sprinkled on an apple sauce
`and the whole amount of apple sauce should be administered.
`Dose adjustments are not recommended in patients with mild and
`moderate renal impairment. Dose in patients with severe renal
`impairment should start with at least
`the recommended dose and
`further adjustment made based on clinical response, since exposures
`would be higher at the recommended doses. SHP465 is not
`recommended for patients with End Stage Renal Disease (ESRD).
`
`Increased gastric pH due to concomitant use of a gastric pH
`modulator may change the exposure and pharmacokinetic profile of
`amphetamine. Frequently monitoring patients for changes in clinical
`effect is recommended. Adjust therapy based on clinical response.
`
`D- and l- amphetamine exposures (AUC, Cmax) are similar (i.e.,
`meeting BE criteria), even though the pharmacokinetic profiles are
`different, after administration of equal doses of SHP465 and
`Adderall XR + Adderall IR 8 hours later.
`
`Dosing in specific patients
`
`Bridge between the to be marketed and
`approved reference drug
`
`
`
`OCP recommends that the Sponsor pursue a lower than 12.5 mg strength post-marketing to allow better
`starting dose in pediatric patients 6-12 years. A lower dosage strength may facilitate the use of SHP465 in
`pediatric patients 6 – 12 years old since the current recommended doses result in higher incidence of
`adverse events such as insomnia and decreased appetite. Refer to medical review for details of adverse
`event profile after administration of SHP.
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`Reference ID: 4109794
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`(b) (4)
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`1.2 Post-Marketing Requirements and Commitments
`
`PMC or
`PMR
`
`Key Issue(s) to
`be Addressed
`
`.
`
`
`
`DPMC
`
`'PMR
`
`uere is an increasing
`se of amphetamines in
`hildren 4 -5 years old.
`erefore, a PK study in
`his age group will
`I' harmacokinetics
`PK) in children 4—5 ' nfonn dosing and assist
`' u the design of safety
`monitoring plan in the
`safety and efficacy study
`hat is being required by
`medical division.
`
`Key Considerations for
`Desi 1 11 Features
`
`A PK study to fully describe the
`shape of the concentration-time
`curve.
`
`
`
`2. Summary of Clinical Pharmacology Assessment
`
`2.1 Pharmacology and Clinical Pharmacokinetics
`
`SHP465 is a new formulation of amphetamine, a stimulant used to treat Attention Deficit
`Hyperactivity Disorder (ADI-ID). SHP465 is a once-daily, triple-bead, mixed amphetamine salt
`(MAS) combination comprised of sulfate salts of dextroamphetamine and amphetamine with
`dextroamphetamine saccharate and amphetamine aspartate monohydrate.
`M“)
`
`dderall XR, is manufactured by the same
`Sponsor and approved for the treatment of ADI-1D. However, the duration of effect is about 12
`hours. SHP465 is designed to last up to 16 hours. The relative bioavailability study was
`conducted to compare SHP465 with Adderall XR used in combination with MAS IR given 8
`hours later. The pharmacokinetic properties were investigated in single dose and multiple dose
`studies conducted in healthy adult subjects and pediatric patients.
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`Reference ID: 41 09794
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`Pharmacokinetic comparison between SHP465 and Adderall XR + MAS IR
`SHP465 37.5 mg, and ADDERALL XR 25 mg followed by mixed amphetamine salts IR 12.5
`mg administered 8 hours later, were similar (i.e. met BE criteria) with respect to Cmax and
`AUC of d- and l-amphetamine, even though the pharmacokinetic profiles are different (Figure 1
`and Table 1). The mean time to maximum d- and l-amphetamine concentration (Tmax) was
`about 8 hours and 10 hours for SHP465 and Adderall XR + MAS IR, respectively. The
`elimination half-lives of d-amphetamine (10.1 and 9.7 hours for SHP465 and Adderall XR,
`respectively) and l-amphetamine (12.5 and 11.7 hours for SHP465 and Adderall XR,
`respectively) were similar.
`
`Figure 1: Mean d-Amphetamine Plasma Concentrations Over Time After a Single Dose, under
`fasting conditions, of SPD465 or ADDERALL XR
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`
`
`Source: Dr. Andre Jackson review (DARRTS Date: 4/24/2007)
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`Reference ID: 4109794
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`Table 1: Plasma Pharmacokinetic Parameters for d-Amphetamine after a Single Dose of SHP465
`or Adderall XR + Mixed Amphetamine Salts (IR) Administered 8 hours later- PK Population
`
`
`
`Source: Dr. Andre Jackson review (DARRTS Date: 4/24/2007)
`
`
`Pharmacokinetics of SHP465
`
`The Sponsor utilized population PK analyses to estimate apparent clearance and apparent volume
`of distribution for both d-amphetamine and l-amphetamine utilizing sparse and rich PK data
`obtained from adults as well as pediatric patients age 7 to 17 years. The apparent clearance of d-
`amphetamine and l-amphetamine is 25.2 L/h and 23.7 L/h, respectively. Following a 12.5 mg
`single dose of SHP465, for both d-amphetamine and l-amphetamine, children (age 7-12 years)
`have 44% higher and 77 - 83% higher Cmax than adolescents (age 13-17 years) or adults,
`respectively. Also, for this dose, children also have a 39-46% higher and 101-102% higher
`AUC0-24 than adolescents or adults, respectively, receiving the same dose. For both isomers, the
`apparent clearance and apparent volume increase as body weight increases. There was no
`significant relationship between age and gender on the Cl/F and V/F of d- or l-amphetamine,
`after adjusting body weight.
`
`The exposures to both d- and l-amphetamine, as presented by Cmax and AUC(0-24) at steady
`state, increased with increasing SHP465 doses. The increases were dose-proportional across the
`dose range of 12.5 to 75 mg. Consumption of a high fat meal slows SHP465 absorption
`(increases median Tmax by about 5 hours) but does not affect the Cmax and AUC. Therefore,
`SHP465 can be taken without regard to meals. However, given the shape of pharmacokinetic
`profile change with high fat meal and the strong concentration-response relationship, patients
`should be advised to take the dose constantly either with food or without food to ensure
`consistent clinical response over time.
`
`SHP465 pharmacokinetics (Cmax and AUC data for both d- and l-amphetamine) are not affected
`by whether the capsule was consumed intact or if the contents of the capsule were sprinkled onto
`an apple sauce.
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`Reference ID: 4109794
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`There was an approximately 1.5-fold increase in the exposures to both d- and l-amphetamine
`following the seventh daily SHP465 dose when compared with a single oral dose of 12.5 mg.
`Based on statistical comparisons of predose d- and l-amphetamine concentrations, steady-state
`was attained between Day 5 and 8 of dosing.
`
`
`2.2 Dosing and Therapeutic Individualization
`
`2.2.1 General Dosing
`SHP465 is to be administered once daily with or without food. The content of the capsule can be
`sprinkled on an apple sauce and administered. Patients should be consistent on taking the product
`either with or without food every time to ensure consistent clinical response over time.
`
`The recommended starting dose in adults 18 to 55 years is 12.5 mg once daily in the morning
`upon awakening. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly to a
`maximum dose of 50 mg/day.
`
`The recommended starting dose in children 13 to 17 years old is 12.5 mg daily in the morning
`upon awakening. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly to a
`maximum dose of 25 mg/day
`
`Sponsor provided efficacy and safety results from Phase 3 trials (Studies 305 and 306) in order to
`support the proposed therapeutic dose regimens. Please refer to the medical officer’s review for
`Agency’s evaluation and conclusions
`
`2.2.2 Therapeutic Individualization
`
`Dosing in Renal Impairment
`No dedicated renal impairment studies were conducted with SHP465, which contains both d- and
`l-amphetamine. The sponsor referred to a study conducted with lisdexamphetamine, which may
`be converted to d-amphetamine, as the basis for recommending dosing of SHP465 in patients
`with renal impairment.
`
`The disposition of d-amphetamine after administration of lisdexamphetamine (Vyvanse ®
`manufactured by the same sponsor) is expected to be similar to that after administration of
`SHP465 if the pharmacokinetics of lisdexamphetamine is unaffected by renal impairment. A
`renal impairment study conducted with lisdexamphetamine in subjects with various degrees of
`renal impairment indicated the exposures to d-amphetamine and lisdexamphetamine were not
`significantly increased in patients with mild to moderate renal impairment. Patients with severe
`renal impairment showed approximately 2 fold increase in d-amphetamine with no apparent
`increase in lisdexamphetamine exposure. The lisdexamphetamine and d-amphetamine data
`collected from ESRD subjects are limited and with high variability. Some subjects showed a
`high concentration of lisdexamphetamine with extremely low concentration of amphetamine,
`suggesting possible inability of these patients to convert lisdexamphetamine to amphetamine in
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`Reference ID: 4109794
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`this population. Some subjects demonstrated high pre-dose lisdexamphetamine concentration
`level with no clear explanation. Hence, the data in ESRD is inconclusive to make dosing
`recommendation.
`
`
`The effect of renal impairment on exposure to l-amphetamine in adults and pediatric patients
`aged 13 -17 years is not known. Mechanistically, if the changes in d-amphetamine observed in
`patients with mild to severe renal impairment receiving lisdexamphetamine is mainly due to
`glomerular filtration, we would anticipate that l-amphetamine show similar change with d-
`amphetamine. It is possible that metabolic enzymes and renal active transporters may be
`involved in the elimination of d- or l-amphetamine. These enzymes and renal active transporters
`may show selectivity on different stereoisomers which may be enhanced in patients with
`compromised renal function. The pharmacokinetic profiles of d- and l-amphetamine with a
`consistent ratio across various time points do not appear to directly suggest the existence of this
`selectivity. It is still feasible that the selectivity may be more apparent in patients with
`compromised renal function than in patients with normal renal function. However, it is to note
`that l-amphetamine seems to account for approximately 25% of the total circulating
`amphetamine (d- and l-amphetamine in combination). Therefore, we anticipate that the total
`amphetamine exposure change may follow similar trend (at least qualitatively) with d-
`amphetamine in patients with mild to severe renal impairment, even though there might be some
`quantitative deviation.
`
`Overall, the recommendations for dosage adjustment in patients with compromised renal
`function following the administration of SHP465 may be derived mainly based on d-
`amphetamine changes in various renal impairment patients, which are (1) no dosage adjustment
`in patients mild to moderate renal impairment, (2) reduced dose initially by half in patients with
`severe renal impairment (Given the uncertainty of the quantitative change on total amphetamine,
`further dosage adjustment may be required), and (3) no recommendation of usage in ESRD.
`
`Dosing in Hepatic Impairment Patients
`Formal studies in patients with hepatic impairment were not conducted.
`
`2.3 Outstanding Issues
`The review team voiced concerns regarding tolerability of the proposed 12.5 mg starting dose in
`pediatric patients, particularly in children 6 to 12 years of age, observed in Phase 3 trials. In the
`Phase 3 trial, the incidence of adverse events such as insomnia and loss of appetite are higher in
`pediatric patients 6 -12 years than adults and pediatric patients 13 – 17 years old. Higher
`exposures were observed in pediatric patients 6 -12 years than in adults or pediatric patients 13 -
`17 years. Refer to medical review for details of adverse events profile. While data were not
`available to assess exposure-safety relationship, single-dose PK determined that children
`experienced greater Cmax and a greater AUC0-24 for both amphetamine isomers following
`administration of single 12.5 mg Mydayis capsules (median d-amphetamine Cmax of 27.6 ng/mL
`and 16.71 ng/mL, in children and adults, respectively; median d-amphetamine AUC0-24 of 419
`hr*ng/mL and 226 hr*ng/mL, in children and adults, respectively). However, as there is not
`currently a lower dose level available, and as it is not appropriate to recommend splitting the
`
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`Reference ID: 4109794
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`9
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`12.5 mg capsule, a dose reduction below 12.5 mg during initiation cannot be recommended.
`Therefore, SHP465 is not recommended for use in pediatric patients 6 -12 years of age. OCP
`supports the decision to limit the use of SHP465 in patients 13 years and older. In addition, OCP
`recommends that the sponsor pursues a lower dose level post-marketing
`
`Pharmacokinetic Studies in Children 4 -5 years old. This study would be requested as a Post
`Marketing Requirement (PMR)
`
`2.4 Summary of Labeling Recommendations
`General dosing recommendation is acceptable for patients 13 years and above.
`
`Not recommended for use in pediatric patients 12 years and younger.
`Adult patients with severe renal impairment patients (GFR 15 – < 30 mL/min/1.73 m2) should
`start at the recommended starting dose with a maximum of dose of at least half of the
`recommended dose for patients without renal impairment.
`
`It is recommended that pediatric patients with severe renal impairment take 12.5 mg per day if
`tolerable. Dose escalation is not recommended in pediatric patients 13 – 17 years with severe
`renal impairment.
`Not recommended for use in patients with ESRD (GFR < 15 mL/min/1.73 m2) .
`
`Caution should be exercised when administering a pH modulator (e.g., proton pump inhibitor or
`H2 blocker) concomitantly with SHP465. Frequent monitoring is recommended and therapy
`adjusted based on clinical response.
`
`SHP465 can be administered with or without food; however, patients should be advised to take it
`constantly either with or without food for consistent clinical response.
`
`3. Comprehensive Clinical Pharmacology Review
`3.1 Overview of the Product and Regulatory Background
`
`This submission is a complete response to an approvable letter that was issued for NDA 22063 in
`May 2007. The approvable letter tentatively approved 12.5 and 25 mg SHP465 for the treatment
`of Attention Deficit Hyperactivity Disorder (ADHD). The clinical development program
`consisted of 16 clinical studies, 13 of which were included in the original NDA, and 3 of which
`are new and included in this resubmission. The resubmission includes the following studies
`
`Study SHP-111: A Phase 1, open-label study of the pharmacokinetics of d- and l-amphetamine
`after a single oral dose of SHP465 12.5 mg or 25 mg administered to children and adolescents
`aged 6 to 17 years with ADHD.
`
`Study SHP465-305: A Phase 3, randomized, double-blind, multicenter, placebo controlled,
`dose-optimization, safety and efficacy study of SHP465 in children and adolescents aged 6 to 17
`years with ADHD.
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`Reference ID: 4109794
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`Study SHP465-306: A Phase 3, randomized, double-blind, multicenter, placebo-controlled,
`forced-dose titration, safety and efficacy study of SHP465 in adults aged 18 to 55 years with
`ADHD.
`
`A population PK analysis was also included in the resubmission. No formal drug-drug
`interaction studies (regarding pharmacokinetics and pharmacodynamics) were conducted. The
`sponsor stated that all information on drug-drug interaction potential of amphetamine is
`potentially applicable to SHP465.
`
`SHP465 is a once-daily, triple—bead, sustained release, single-entity, mixed amphetamine salt
`product for oral administration, and is comprised of sulfate salts of dextro- and levo-
`amphetamine, with dextroamphetamine saccharate and amphetamine aspartate monohydrate.
`SHP465 capsules contain 3 types of drug—releasing beads, which provide immediate release (IR),
`pulsatile delayed release (DRl), and delayed sustained release (DR2) of the mixed amphetamine
`salts.
`M“)
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`The sponsor developed SHP465 sustained release formulation to provide
`a once-daily preparation designed to provide symptom coverage up to 16 hours post-
`administration.
`
`In addition to Phase 1 formulation studies and completed Phase 2 duration studies in
`adults and adolescents to demonstrate duration of effect between 2 and 16 hours; two pivotal
`Phase 3 studies were included in the original NDA (SPD465-301 and SPD465—303) that
`evaluated the efficacy and safety of different dose regimens of SHP465 in adults. SPD465-301
`used a double-blind design, and all subjects completed a dose-optimization phase of SHP465
`doses starting at 12.5 mg up to 75 mg followed by a dose-maintenance phase. This sequence was
`designed to maximize symptom control while minimizing adverse events (ABS). Study SPD465-
`303 used a forced-dose design in which adults were randomized to either SHP465 (25, 50, or 75
`mg) or placebo. Study SPD465-304 was conducted to assess long-term safety (out to 1 year) and
`maintenance of efficacy of doses.
`
`The 3 additional clinical studies included in the resubmission were designed to finther explore
`the dose range in adults and evaluate the pharmacokinetics, safety, and efficacy beyond the
`classroom study of SHP465 in adolescents to the broader pediatric population (6-17 years old).
`Study SHP465-111 assessed pharmacokinetic properties in single dose and multiple doses of
`12.5 and 25 mg in children and adolescent patients with ADHD. Studies SI-IP465-305 and
`SHP465-306 assessed the efficacy and safety of SHP465 in subjects diagnosed with ADHD.
`Study SHP465-306 was conducted in adults aged 18-55 years and evaluated fixed doses of 12.5
`and 37.5 mg, and SHP465-305 was conducted in children and adolescents aged 6-17 years and
`evaluated SHP465 fixed doses of 12.5 and 25 mg.
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`Reference ID: 41 09794
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`3.2 General Pharmacological and Pharmacokinetic Characteristics
`Pharmacology
`Mechanism of action
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`Active moieties
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`QT Prolongation
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`General Information
`Bioanalysis
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`Drug Exposure at steady state
`following the therapeutic dosing
`regimen
`Maximum tolerated dose or exposure
`Dose Proportionality
`Accumulation
`Absorption
`
`
`Distribution
`Elimination
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`Reference ID: 4109794
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`Amphetamine is non-catecholamine sympathomimetic
`amines. Exact mechanism of action in ADHD is not
`known
`Mixed Amphetamine Salts: Neutral sulfate salts of
`dextroamphetamine and amphetamine, amphetamine
`aspartate monohydrate
`The potential of QT prolongation after administration of
`amphetamine products is not known.
`
`LC/MS/MS
`Assay Range: 0.5 – 75 ng/mL; 0.1 – 100 ng/mL
`Steady state reached between Day 5 and 8
`
`75 mg
`12.5 mg to 75 mg
`R = 1.5
`Time to maximum concentration (Tmax) about 8 hours
`Effect of Food: Tmax delayed by about 5 hours but
`Cmax and AUC for both d and l-amphetamine not
`affected after administration with a high fat meal.
`Co-administration with apple sauce did not affect
`exposure or prolong Tmax.
`Protein Binding about 40%
`Mean T ½ is approximately 10 – 12.5 hours
`Metabolism: CYP2D6, Flavin containing
`monooxygenase 3 (FMO) and dopamine β-hydroxylase
`Amphetamine is not inhibitor in vitro of CYP1A2,
`CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19,
`CYP2D6, and CYP3A4 in human hepatic
`microsomal suspensions, nor was it an in vitro inducer
`of CYP1A2, CYP2B6 or CYP3A4/5 in cultured fresh
`human hepatocytes. Amphetamine is not an in vitro
`substrate for permeability glycoprotein (P-gp) in vitro
`inhibitor of P-gp.
`Excretion: Renal
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`3.3 Clinical Pharmacology Questions
`
`3.3.1 To what extend does the available clinical pharmacology information provide pivotal or
`supportive evidence of effectiveness?
`In all 3 Phase 2 studies, the efficacy and duration of effect were determined using the PERMP, a
`skill-adjusted math test administered before and at 2, 4, 8, 12, 14, and 16 hours after dosing in
`the controlled environment of either an Adult Work Place Laboratory setting or a classic
`classroom analog.
`
`The primary efficacy endpoint for the Phase 2 studies submitted in the original application was
`the average PERMP total scores over Classes 1-6 and at each time point from 2 through 16 hours
`post dose in the PERMP total scores. In the Phase 3 studies, the primary efficacy outcome was
`based on clinician administered ADHD-RS-IV total scores, which were assessed weekly during
`the 6-week double-blind treatment period. SHP465 demonstrated a significant treatment effect
`in each of the 3 randomized treatment groups (25, 50, or 75 mg) compared with placebo on the
`primary efficacy endpoint, ADHD-RS-IV total score (p<0.0001) and key secondary efficacy
`endpoint, CGI-I (p<0.0001).
`
`Study SHP465-306, the new safety and efficacy study, examined the efficacy and safety of
`SHP465 (forced-dose titration) vs placebo in adults with ADHD. In this parallel-group, double-
`blind, Phase 3 study, subjects were randomized 1:1:1 to receive SHP465 12.5 mg, SHP465 37.5
`mg, or placebo daily for a 4-week treatment period. The primary measure of efficacy was the
`clinician-administered adult ADHD-RS with prompts. The primary efficacy analysis
`demonstrated significantly greater symptom reduction and clinical improvement at Visit 6 (Week
`4) from baseline in subjects diagnosed with ADHD and receiving treatment with both SHP465
`12.5 and 37.5 mg compared with subjects receiving placebo. The difference from placebo was
`larger in the SHP465 37.5 mg than in the 12.5 mg treatment group. According to the sponsor, the
`doses studied were adequate to demonstrate efficacy of SHP. Please refer to Agency’s medical
`review for details of the efficacy and safety analysis.
`
`
`3.3.2 Is the proposed general dosing regimen appropriate?
`Yes, the proposed dosing regimen is acceptable for patients 13 years and older. However, it does
`not appear to be appropriate to use SHP464 in pediatric patients 6 to 12 years of age with the
`currently proposed dosing regimen because for a given dose, exposures in these children are
`higher than pediatric children 13 -17 years and adults. Also, insomnia and loss of appetite are
`higher in pediatric patients 13 -17 years and adults.
`
`The proposed dosing regimen in patients 13 years and older is acceptable. Based on the clinical
`pharmacology properties and efficacy and safety observations of SHP465, the recommended
`starting dose of 12.5 mg once daily in the morning for adults and pediatric patients 13 -17 years
`old who are either starting treatment for the first time or switching from another medication
`regimen is appropriate. Dosage may be adjusted in increments of 12.5 mg no sooner than weekly
`up to a maximum dose of 50 mg/day, based on the therapeutic needs and response in adult
`patients. The maximum dose in pediatric patients is 25 mg/day. The dose can be taken with or
`
`
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`Reference ID: 4109794
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`13
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`

`

`without food. However, patients are advised to constantly take either with or without food in
`order to ensure consistent clinical response over time. The content of a capsule can be sprinkled
`on apple sauce and the whole amount should be taken.
`
`We recommend that SHP465 not be used in pediatric patients 6 to 12 years of age. There are
`concerns regarding the tolerability issues which may arise from administering the same initial
`dose during titration, 12.5 mg once daily, to children 6 to 12 years of age as is proposed for
`adults. A single dose of 12.5 mg SHP465 produced higher Cmax and AUCM4 values in children
`6 to 12 years of age than in adults (Figure 2 and Figure 3). The same trend of higher Cmax and
`AUCo_24 in pediatric patients 6 to 12 years of age compared to adults is seen for the l-
`amphetamine isomer as well.
`
`Figure 2: Comparison of d—amphetamine Cmax Distribution following a Single 12.5 mg
`
`Capsule Administered to adults or Pediatric Patients age 7 to 12 years.
`
`
`9
`
`9 3
`
`5
`
`
`
`(nymL) 25Cmax
`
`
`
`15 E:
`
`l
`Hen-yum: (age 1951)
`
`l
`mum: Pm (age 7-12)
`
`mmmsuues 107“ Mommiunsmyn
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`Reference ID: 41 09794
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`14
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`

`

`Figure 3: Comparison of d-amphetamine AUC0_24 Distribution following a Single 12.5 mg
`
`Capsule Administered to adults or Pediatric Patients age 7 to 12 years.
`K’J
`
`AUG0-24hm(hrnymL)
`
`§
`
`
`
`HealhyAdlls (age 19.51)
`
`Pedal“: Patients (age 1.12)
`
`Ml‘dahfiomShdies 107m 110.Pediatlicdataiom$trny11
`
`Consistent with the increased exposure in pediatric patients 6 to 12 years of age, it was observed
`
`in Phase 3 studies that the incidence of adverse events such as insomnia and loss of appetite
`
`were higher in pediatric patients aged 6 -12 years old compared to adults or pediatric patients age
`
`13 -17 years. Unfortlmately, there is insufficient data to formally assess the relationship between
`
`adverse event rate and amphetami