022063Orig1s000

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER: 022063Orig1s000

OTHER REVIEW(S)

Reference ID: 4119537

Reference ID: 4119537 MEMORANDUM REVIEW OF REVISED LABEL AND LABELING Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Review: June 20, 2017 Requesting Office or Division: Division of Psychiatry Products (DPP) Application Type and Number: NDA 022063 Product Name and Strength: Mydayis (Mixed Salts of a Single-Entity Amphetamine) (b) (4) release capsule 12.5 mg, 25 mg, 37.5 mg, 50 mg Product Type: Single-Ingredient Product Rx or OTC: Rx Applicant/Sponsor Name: Shire Development LLC Submission Date: December 20, 2016 OSE RCM #: 2017-125-2 DMEPA Primary Reviewer: Briana Rider, PharmD DMEPA Team Leader: Lolita White, PharmD

1 PURPOSE OF MEMO The Division of Psychiatry Products (DPP) requested that we review the revised container labels for Mydayis (Appendix A) to determine if they are acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 CONCLUSION The revised container labels for Mydayis are acceptable from a medication error perspective. We have no further recommendations at this time.

a Rider B. Label and Labeling Review Memorandum for Mydayis (NDA 022063). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2017 JUN 19. RCM No.: 2017-125-1. 1

Reference ID: 4113842 APPENDIX A. LABEL AND LABELING SUBMITTED ON JUNE 20, 2017 Container Label: 12.5 mg (b) (4)

Reference ID: 4113842 Container Label: 37.5 mg (b) (4)

Reference ID: 4113842 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------BRIANA B RIDER 06/20/2017

LOLITA G WHITE 06/21/2017

Reference ID: 4113842 MEMORANDUM REVIEW OF REVISED LABEL AND LABELING Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

Date of This Review: June 19, 2017 Requesting Office or Division: Division of Psychiatry Products (DPP) Application Type and Number: NDA 022063 Product Name and Strength: Mydayis (Mixed Salts of a Single-Entity Amphetamine) (b) (4) release capsule 12.5 mg, 25 mg, 37.5 mg, 50 mg Product Type: Single-Ingredient Product Rx or OTC: Rx Applicant/Sponsor Name: Shire Development LLC Submission Date: December 20, 2016 OSE RCM #: 2017-125-1 DMEPA Primary Reviewer: Briana Rider, PharmD DMEPA Team Leader: Lolita White, PharmD

1 PURPOSE OF MEMO The Division of Psychiatry Products (DPP) requested that we review the revised container labels for Mydayis (Appendix A) to determine if it is acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a

2 CONCLUSION The revised container labels are unacceptable from a medication error perspective. In a previous label and labeling review,a we expressed concern that Mydayis may be inappropriately substituted for Adderall XR since both products have the same established name, have an overlapping strength of 25 mg, and are both dosed once daily. We have since considered several potential strategies to help differentiate the container labels from those of Adderall XR.

a Rider B. Label and Labeling Review for Mydayis (NDA 022063). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2017 MAY 18. RCM No.: 2017-125. 1

Reference ID: 4113248 After consultation with OGD, OCC, and OPDP we have determined that the addition of the statement ‘Do not substitute for Adderall XR’ to the Principal Display Panel (PDP) of the Mydayis container labels would be appropriate to help minimize the risk of wrong drug medication errors.

3 RECOMMENDATIONS FOR SHIRE DEVELOPMENT LLC We recommend the following be implemented prior to approval of this NDA: A. As presented, the container labels do not adequately convey to the end user that the product is not substitutable for Adderall XR. We are concerned that Mydayis may be inappropriately substituted for Adderall XR products since Mydayis and Adderall XR have the same established name, have an overlapping dose of 25 mg and are both dosed once daily. We recommend that you add the following statement to the Principal Display Panel on the container labels under the net quantity statement. i. Do not substitute for Adderall XR.

Reference ID: 4113248 APPENDIX A. LABEL AND LABELING SUBMITTED ON JUNE 6, 2017

Container Label: 12.5 mg (b) (4)

Reference ID: 4113248 Container Label: 37.5 mg (b) (4)

Reference ID: 4113248 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------BRIANA B RIDER 06/19/2017

LOLITA G WHITE 06/19/2017

Reference ID: 4113248 M E M O R A N D U M Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research

Date: June 20, 2017

To: Mitch Mathis, MD, Director Division of Psychiatry Products (DPP)

Through: Silvia Calderon, Ph.D., Senior Pharmacologist Martin Rusinowitz, M.D., Senior Medical Officer Controlled Substance Staff

From: Edward Hawkins, PhD, Pharmacologist Controlled Substance Staff

Subject: SHP 465 (mixed salts of a single entity amphetamine), NDA 22-063 Trade Name, dosages, formulations, routes: Mydayis capsules, 12.5 mg, 25 mg, 37.5 mg, and 50 mg, for oral administration once a day IND Number: 58,037 Indication(s): Treatment of attention deficit hyperactivity disorder (ADHD) Sponsor: Shire PDUFA Goal Date: June 20, 2017

Materials Reviewed:

• 1.14.1.3 Draft labeling text • 1.16.1 Abuse potential evaluation report • 2.3 Drug product and substance • 2.7 Clinical summary • 5.3.3 Reports of human PK studies • 5.3.5 Reports of efficacy and safety studies

Table of Contents I. SUMMARY ...... 3 1. Background...... 3 2. Conclusions...... 3 3. Recommendations...... 4 II. DISCUSSION...... 5 1. Chemistry...... 5

Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

1.1 Substance Information...... 5 1.2 Potential Drug Isomers...... 7 1.3 In Vitro Manipulation and Extraction Studies for Products with Abuse-Deterrent Features ..7 2. Nonclinical Pharmacology...... 7 3. Clinical Pharmacology...... 8 3.1 Absorption, Distribution, Metabolism, Elimination (ADME) ...... 9 3.2 Drug/Product Interactions ...... 9 4. Clinical Studies...... 10 4.1 Human Abuse Potential Studies...... 11 4.2 Adverse Event Profile Through all Phases of Development...... 11 4.3 Safety Profile...... 13 4.4 Evidence of Abuse, Misuse and Diversion in Clinical Trials ...... 13 4.5 Tolerance and Physical Dependence Studies in Humans...... 14 5. Regulatory Issues and Assessment ...... 14 III. REFERENCES ...... 16

I. SUMMARY

1. Background This memorandum responds to a consult request by the Division of Psychiatry Products (DPP) to evaluate abuse-related preclinical and clinical data submitted by Shire for pending NDA 22-063 (and associated IND 58,037) for Mydayis (Mixed salts of a single-entity amphetamine) capsules. This product (SHP465) is a mixed formulation of sulfate salts of dextroamphetamine and amphetamine. SHP465 is a capsule that is formulated using beads that release drug in a pulsatile format: immediate release (IR), pulsatile delayed release (DR), and delayed (b) (4) release (DR1). This triple bead formulation is designed to provide a therapeutic dose of the mixed amphetamine salts (MAS) over the course of 16 hours. A typical dosing regimen for ADDERALL requires a morning dose of extended release (XR) followed 8 hours later by an immediate release (IR) capsule. The SHP465 capsule is being designed to be administered orally once per day in doses of 12.5 mg, 25 mg, 37.5 mg, or 50 mg. The drug product is being developed to treat attention deficit hyperactivity disorder (ADHD). The recommended dose is to titrate high enough to treat the symptoms of ADHD and while minimizing side effects. The dose of ADDERALL in children and adolescents 6-17 years of age is typically higher than that required by adults ≥18 years old.

Amphetamine is a potent central nervous system (CNS) stimulant of the phenethylamine class that has extensive use in the treatment of ADHD, narcolepsy, and obesity. There are many pharmacological effects of amphetamine that result in a behavioral response indicative of CNS stimulation. In general, amphetamine increases monoamine signaling by increasing the release of monoamines from presynaptic terminals, delaying the clearance of monoamines from the synaptic cleft and inhibiting monoamine Page 2 of 17

Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

oxidase [1]. The monoamines that are most greatly affected in relation to the treatment of ADHD are norepinephrine (NE) and dopamine (DA); however, an increase in serotonin (5-HT) is also present. This effect is through the reuptake inhibition at the NE, DA, and 5-HT transporters or NET, DAT, and SERT, respectively.

Amphetamine products were first accepted for the treatment of ADHD by FDA in 1943. There are now many approved amphetamine-containing drug products on the market to treat ADHD, obesity, or narcolepsy. Amphetamine, its salts, and isomers, were placed in Schedule III (C-III) upon creation of the CSA in 1970. In 1971, amphetamine, its salts and isomers, were moved into Schedule II (C-II) of the CSA as a result of its high potential for abuse and its accepted medical use (36 FR 12734), and amphetamine remains listed in C-II.

2. Conclusions

• Mydayis, or SHP465, contains mixed amphetamine salts listed in Schedule II of the CSA. The Sponsor has not requested a change in schedule. • The 50 mg dose of Mydayis, the highest to-be-marketed dose, will contain 31.3 mg of amphetamine base (dextro and levo isomers). This is higher than the highest currently marketed dose of ADDERALL XR at 30 mg which contains18.8 mg of amphetamine base. • The desired pharmacokinetic profile of the formulation was modeled after a 20 mg dose of Adderall XR® followed by a 10 mg dose of ADDERALL® administered 8 hours later. • The Sponsor did not conduct nonclinical or clinical abuse related studies for SHP465 • The Sponsor states that SHP465 does not have abuse-deterrent properties • Dissolution studies aimed to characterize the effects of alcohol on the dissolution of SHP 465 indicated 80% dissolution of a 50 mg capsule was observed at 2 hours in 40 % ethanol, whereas only 33 % dissolution was seen when using dissolution media without ethanol (Media 1: 750 mL dilute hydrochloride acid ). A second study showed that the addition of 20% or 40% ethanol in the media dissolved the 50 mg in 30 minutes. • Results from dissolution studies should not be viewed as representative studies of the amounts of amphetamine that may be extracted from the product using different experimental conditions (solvents, heat, agitation), as these studies are conducted using high volumes of solvent and under compendia test conditions. • Adverse events from phase 3 clinical studies that are related to abuse were negligible • There is no evidence of abuse, misuse, or diversion of SHP465 in any of the clinical trials • No tolerance or physical dependence studies were conducted by the Sponsor • Although ADDERALL XR is listed as the reference product, the Mydayis label is modeled after the label for Dyanavel, which was recently updated. In reviewing these labels CSS became aware that these labels have not been updated to be in accordance with current 2017 guidance (Guidance for Industry, Assessment of Abuse Potential of Drugs, January2017, https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 198650.pdf). A class wide revision regarding Section 9 of the label for CNS stimulants may be necessary to address inconsistencies between labels and clarify definitions

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Reference ID: 4110964

Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

Physical dependence (a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including MYDAYIS. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include extreme fatigue and depression.

II. DISCUSSION

1. Chemistry

1.1 Substance and Product Information

The active pharmaceutical ingredients (API) of SHP465 is a mixture of 4 amphetamine salts: amphetamine sulfate United States Pharmacopoeia (USP), dextroamphetamine sulfate USP, dextroamphetamine saccaharate and amphetamine aspartate monohydrate. The enantiomeric ratio of d- amphetamine to l-amphetamine is the same as the already approved ADDERALL XR, 3:1 respectively.

The chemical properties of the 4 substances are similar. All are white to off-white crystalline powders that are soluble in water. The following information lists the chemical name, the chemical abstract service (CAS) registry number, molecular formula (MF), molecular weight (MW) and the structure of each API.

Amphetamine Sulfate, USP Chemical name: ±-α-Methylphenylamine sulfate CAS: 60-13-9 MF: C9H13N• H2SO4 MW: 368.50 g/mol Structure:

•

Dextroamphetamine Sulfate, USP Chemical name: +-α-Methylphenylamine sulfate CAS: 51-63-8 MF: C9H13N• H2SO4 MW: 368.50 g/mol Structure:

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Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

•

Dextroamphetamine Saccharate Chemical name: +-α-Methylphenylamine saccharate CAS: 350708-40-6 MF: C9H13N• C6H10O8 MW: 480.56 g/mol Structure:

•

Amphetamine aspartate monohydrate Chemical name: +-α-Methylphenylamine aspartate monohydrate CAS: 350708-35-9 MF: C9H13N• C4H7NO4 MW: 286.33 g/mol Structure:

• • H2O

SHP465 is currently designed to be oral capsules for once daily administration in strengths of 12.5 mg, 25 mg, 37.5 mg, and 50 mg. SHP465 capsules contain equal amounts (by weight) of four salts: dextroamphetamine sulfate and amphetamine sulfate, dextroamphetamine saccharate and amphetamine aspartate monohydrate. This results in a (b) (4) mixture of dextro- to levo- amphetamine base equivalent.

Similar to ADDERALL XR® (reference NDA 21-303), SPD465 capsule strengths are expressed in terms of mg of amphetamine salt, not mg of amphetamine base. Thus, the total amphetamine base equivalent for each previously mentioned capsule are 7.8 mg, 15.6 mg, 23.5 mg, and 31.3 mg, respectively. Each of the four amphetamine salts are evenly distributed into a release system that is composed of three different types of beads which are inserted into the capsule. Three types of beads are contained in each capsule: immediate release (IR), pulsatile-delayed release (DR) and delayed (b) (4) released (DR1). The capsule is designed to release one third of the total dose immediately (IR), one third by pulsatile-delayed release (DR) and one third by delayed (b) (4) released (DR1).

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Reference ID: 4110964

Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

The psychostimulant effects of amphetamine are postulated to result from the increase in dopamine release from the mesolimbic regions of the central nervous system [4]. The behavioral and abuse related effects of amphetamine have been studies for almost 100 years [5]. Several reviews have also been published which document the stimulant effects and abuse potential of amphetamine and its salts [1]. In brief, drug discrimination assays conducted in rats trained to discriminate amphetamine (0.5 mg/kg, i.p.) from vehicle determined that several other stimulants generalized to the amphetamine cue. In order of potency these were: methamphetamine, methylphenidate, fencamfamine, mazindol, nomifensine, amfonelic acid, cocaine, and buproprion [6]. Furthermore, amphetamine, given either orally or through intramuscular injections, fully generalized to cocaine in rhesus monkeys trained to discriminate cocaine from vehicle [7].

Self-administration studies are conducted to measure the reinforcing effects of a drug. A study conducted by Risner (1975) determined that both the d- and the l- isomers of amphetamine are self- administered. This study further determined that the d- isomer is more potent than the l- isomer of amphetamine with (b) (4) mg of the d- isomer having the same reinforcing effect as (b) (4) of the l- isomer [8]. As a result, amphetamine and its salts have a very well characterized abuse profile as a stimulant with high reinforcing effects. Amphetamine is a phenethylamine that is listed in Schedule II of the CSA.

3. Clinical Pharmacology

The Sponsor conducted several clinical pharmacology studies. Among those was one to evaluate the pharmacokinetics of 37.5 mg of SHP465 relative to 25 mg ADDERALL XR followed by a 12.5 mg dose of IR MAS administered after 8 hours. This study (SPD465-103) was an open-label, randomized, single-dose, two-period, two-treatment crossover study. The study was conducted in a total of 20 subjects; 8 males and 12 females. SPD465 had a single peak at a Tmax of 8 hours for both d- and l- amphetamine. Table 1 below shows the measured PK values for d- and l- amphetamine demonstrating the bioequivalence of SHP465 37.5 mg to 25 mg ADDERALL XR followed by a 12.5 mg dose of IR MAS administered after 8 hours. The Cmax, Tmax and area under the curve values are within the FDA guidelines for measuring bioequivalence (BE). The FDA Guidance for Statistical Approaches to Establishing Bioequivalence recommends that the confidence intervals to determine BE typically be between 80-125% for the ratio of the product averages. Furthermore, when looking at a graph of the plasma concentration (ng/mL) vs. time (hours) the drugs follow a similar time course. The curve for ADDERALL XR has two peaks because a second dose of IR was given 8 hours after the XR. ADDERALL is typically dosed in this manner in real world situations and the Sponsor’s aim is to replace this twice a day dosing with a single dose. Table 1 shows the PK parameters measured in this clinical study. The PK values for SHP465 are within the guidelines set forth by FDA to determine BE. Therefore, one dose of 37.5 mg SHP465 is BE to 25 mg ADDERALL XR followed by a 12.5 mg dose of IR MAS administered after 8 hours.

The results of the aforementioned study were also confirmed in a clinical PK study (SPD465-110). Clinical study SPD465-110 was conducted to determine if consumption of a high fat meal delays absorption of SHP465. The Tmax was delayed by approximately 5 hours with a high fat diet; however, the Cmax and the AUC were unaffected by the consumption of food.

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Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

These data indicate that SHP465 has a similar pharmacokinetic profile as ADDERALL XR and would therefore be assumed to have a similar abuse potential.

Table 1 Plasma PK for Clinical study SHP465-103 (Table reproduced from NDA 22-063 2.6.7 Synopsis of Individual Studies, Pg 20)

Synopsis Table I: Plasma Pharmacokinetic Parameters for d- and l-Amphetamine After a Single Dose of SPD465 or ADDERALL XR + Mixed Amphetamine Salts 8 Hours Later

ADDERALL XR + Mixed SPD465 37.5mg (A) Parameters amphetamine salts IR 12.5mg (B) Exponentiated 90% CI LS Mean LS LS Ratio % (A)/(B) n Mean (±SD) n Mean (±SD) Mean Mean d-Amphetamine

Cmax (ng/mL) 20 50.3 (7.5) 49.7 19 49.3 (7.4) 49.2 101.0 (96.9, 105.3) AUC (0-last) 20 1058.0 (184.5) 1042.4 19 997.9 (172.9) 1000.8 104.2 (100.2, 108.3) (ng hr/mL) AUC (0-inf) 20 1084.9 (196.2) 1067.8 19 1019.5 (181.3) 1022.5 104.4 (100.3, 108.7) (ng hr/mL)

t1/2 (hr) 20 10.1 (1.3) 19 9.7 (1.2) l-Amphetamine

Cmax (ng/mL) 20 14.7 (2.2) 14.6 19 16.0 (2.3) 16.0 90.9 (87.5, 94.4) AUC (0-last) 20 353.5 (66.0) 347.6 19 364.1 (66.5) 364.6 95.3 (91.0, 99.8) (ng hr/mL) AUC (0-inf) 20 372.8 (73.5) 365.9 19 382.3 (69.0) 383.9 95.3 (91.2, 99.6) (ng hr/mL)

t1/2 (hr) 20 12.5 (1.7) 19 11.7 (1.6) LS=Least squares

3. 1 Absorption, Distribution, Metabolism, Elimination (ADME)

The Sponsor did not conduct studies to assess the ADME of SHP465. The ADME of amphetamine and its salts is well known and characterized [9]. For purposes of abuse, amphetamines are absorbed quickly and distribute throughout the body causing activation of the central and peripheral nervous systems. Amphetamines are metabolized by the P450 (CYP2D6) and flavin monooxygenase systems generating several active metabolites. Amphetamine has a half-life of approximately 9 hours and is excreted renally.

3.2 Drug/Product Interactions

There is evidence that amphetamine products are being abused. The Sponsor claims that amphetamine is being abused not only through the oral route but through the intranasal and intravenous routes as well. In this regard CSS has consulted the Office of Surveillance and Epidemiology to assess the Page 9 of 17

Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

prevalence of abuse of amphetamine products through alternative routes and to assess the public health burden of such abuse.

Nevertheless if individuals were to abuse this product through the intranasal route, these individual would to be able to generate a powder for insufflation. For abuse via the intravenous route, individuals would have to be able to extract a sufficient amount of the active pharmaceutical in a solvent suitable for injection and in a small volume. The Sponsor did not conduct studies to evaluate the feasibility of preparing either a powder for insufflation or a solution for injection.

The Sponsor conducted studies to evaluate the effect of various alcohol concentrations on the dissolution of the product.

The dissolution conditions are outlined in section 3.2.P.5.2 and in section 1.16.1 Abuse Potential Evaluation Report and involve the use of USP paddles at 50 rpm at a temperature of 37 . The Sponsor used solution volumes of 750 to 1000 mLs for the study. The dissolution study for SHP465 tested the 12.5 mg, 25 mg, 37.5 mg, and 50 mg capsules in 0%, 5%, 20%, and 40% ethanol. Two studies were conducted: 1) Study determined the dissolution of the capsules at a series of the different time points (i.e. 0, 2, 3, 4, 6, 8, 10, 12 and 14 hours) and 2) Study was performed in a similar manner for up to 3 hours with smaller time increments. The pH of the dissolution media was altered as a control because the beads are designed to dissolve at specific pHs. From 0-2 hours the pH was 1.1, from 2-3 hours the pH was 6.0, and from 3-14 hours the pH was 7.5. The results are presented in Figure 1.

Figure 1 Dissolution of 50 mg SHP465 tablet over time under conditions of 0, 5, 20 and 40% ethanol (Figure reproduced from NDA 22-063 section 1.16.1 Abuse Potential Evaluation Report, Pg 17)

These results indicate that over 80% of a 50 mg tablet dissolved in 40% ethanol (black) within 3 hours. This is compared to 33% dissolution of the control (blue) without ethanol. These data also suggest that within the first 3 hours the dissolution profile in 5% ethanol was comparable to that in an alcohol free media. To better characterize the first 3 hours the Sponsor conducted another study in which measurements were taken every 15 minutes. The data from the second study was consistent with the data from the first study. Page 10 of 17

Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

4. Clinical Studies

For reference, the following table is from the Sponsor’s submission, listing all clinical studies conducted with SHP465.

Table 1: List of Clinical Studies Conducted by the Sponsor Study ID Phase Design Subject Drug dose Population Single or Age/Sex (Period) range multiple dose 101 1 BA/BE 12 12.5mg healthy multiple 18-55/MF 102 1 BA/BE 20 12.5 -20 healthy multiple 18-55/MF 103 1 PK 20 37.5 healthy multiple 18-55/MF 105 1 BA 16 50 healthy multiple 18-55/MF 106 1 PK 28 12.5-75 healthy single 18-55/MF 107 1 PK 20 12.5-75 healthy multiple 18-55/MF 110 1 PK 18 12.5-75 healthy multiple 18-55/MF 111 1 PK 28 12.5-25 ADHD single 6-17/MF 201 2 PD, 86 25-75 ADHD multiple 18-55/MF efficacy 202 2 PD, 84 25-50 ADHD multiple 18-55/MF efficacy 203 2 PD, 79 25 ADHD multiple 18-55/MF efficacy 301 3 Efficacy 274 12.5-75 ADHD multiple 18-55/MF 303 3 Efficacy 412 25-75 ADHD multiple 18-55/MF 304 3 Efficacy 505 12.5-75 ADHD multiple 18-55/MF 305 3 Efficacy 263 12.5-25 ADHD multiple 6-17/MF 306 3 Efficacy 275 12.5-37.5 ADHD multiple 18-55/MF

4.1 Human Abuse Potential Studies

The Sponsor did not conduct any human abuse potential studies to assess the abuse potential of MAS in humans. The human abuse potential of MAS has been extensively characterized in animals and humans and further study by the Sponsor will not add to the already published information.

The issues related to the abuse of amphetamines have been a problem since the 1930s and are very well known [5]. The development of drug liking scores to assess the positive, negative, and reinforcing effects of drugs were first established in the 1950s using opioids and amphetamines. These scores were used to demonstrate that in human and animal studies amphetamine above a certain dose was not as appealing. Griffith et. al (1975) conducted a study that used 20 or 40 mg of amphetamine and measured stimulation as well as mean drug liking. Interestingly, subjects who took 40 mg had high stimulatory effects but lower drug liking scores [10].

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Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

4.2 Adverse Event Profile Through all Phases of Development

The Sponsor conducted clinical studies in pediatric, adolescent, and adult subjects. Study SHP465-305 was a phase 3 randomized, multicenter, double blind, placebo controlled, dose optimization study in pediatric and adolescent subjects (6-17 years of age) with ADHD. There were 264 subjects enrolled in the study dosed with either 12.5 or 25 mg capsules of SHP465, or placebo. Table 1 below lists the adverse events (AEs) possibly related to abuse in these patients. The AEs do not appear to be of concern. Only irritability had a significantly higher than placebo incidence at 6.2%. This AE is not typically associated with abuse. Table 2 Adverse Events related to abuse in pediatric patients (25 mg SHP465 or placebo)

SHP465 Placebo Preferred Term N=132 n N=131 n (%) (%) Acute psychosis 0 (0) 1 (0.76) Agitation 1 (0.76) 0 (0) Anxiety 2 (1.52) 1 (0.76) Irritability 9 (6.2) 1 (0.76) Somnolence 0 (0) 1 (0.76) Suicidal ideation 0 (0) 1 (0.76) Vertigo 1 (0.76) 0 (0)

The Sponsor also conducted three phase 3 studies in adults to determine the efficacy, tolerability, and safety of SHP465. Table 3 below compiles the list of adverse events related to abuse collected from the three phase 3 clinical trials conducted in adults. Study SPD465-301 was a short term efficacy and safety study that enrolled 274 subjects with ADHD (137 given drug and 137 given placebo). The subjects were given placebo or SHP465 at doses of 12.5, 25, 37.5, 50, 62.5 or 70 mg. Study SPD465-303 was a short term efficacy and safety study that enrolled 412 subjects with ADHD (308 given drug and 104 given placebo). The doses of drug used in this study were 25, 37.5, 50 and 75 mg. Study SPD465-306 was a short term efficacy and safety study that enrolled 275 subjects with ADHD (184 given drug and 91 given placebo). The subjects were given placebo or SHP465 at doses of 12.5 or 37.5 mg.

In general there were very few cases of AEs that are typically associated with abuse of a drug. There is one report of an “accidental overdose”; however, in this case the overdose classification was based on drug accountability discrepancy. The subject stated they could not remember whether or not they had taken their pill that day (which they obviously had) and they took one to be sure. This particular subject was assigned to placebo. This was also the case for a dissociative disorder AE which was mentioned by a subject given a placebo pill and is therefore deemed not related to the drug. One subject did report a case of euphoric mood upon treatment with 50 mg SHP465; however, this is deemed insignificant compared to the number of subjects that received this dose (Table 3). Several other AEs fit into the category of not being reported at a high enough rate to be of concern. These include feeling abnormal (1) and sedation (3). The two major AEs of concern were irritability and auditory hallucination. Amphetamines are known to cause mood changes and can increase irritability, although not dose dependently in these studies. Irritability is typically not considered to be associated with abuse although

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Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

many abused drugs do alter mood. It should be noted that the highest number of reports of irritability were with placebo and lower doses of SHP465 (12.5 and 25 mg) and not at the higher doses of SHP465. With regards to hallucinations, both reports were for auditory hallucinations. For one report, a 21 year old female who received 37.5 mg SHP465 admitted to smoking marijuana the night before the trial. The second report from a subject receiving 75 mg is deemed insignificant compared to the number of patients who took the drug. Furthermore, the 75 mg tablet will not be marketed because no increase in efficacy was seen at this dose above the 50 mg tablet. Table 3 Adverse events related to abuse in adult patients treated with placebo or SHP465

Phase 3 Studies* Adverse Event PBO SHP465 SHP465 SHP465 SHP465 SHP465 Drug PT (N=530) (12.5 mg) (25 mg) (37.5 mg) (50 mg) (75 mg) Overall n (%) [#] (N=185) (N=514) (N=142) (N=482) (N=491) (N=1814) n (%) [#] n (%) [#] n (%) [#] n (%) [#] n (%) [#] n (%) [#] Accidental 1 (0.19) [1] 0 (0) [0] overdose Euphoric mood 1 (0.21) [1] 1 (0.06) [1] Dissociative 1 (0.19) [1] 0 (0) [0] disorder Irritability 11 (2.08) 9 (4.86) [12] 11 (2.14) 3 (2.11) [3] 6 (1.24) [7] 7 (1.43) [8] 40 (2.21) [20] [15] [45] Feeling abnormal 1 (0.20) [3] 1 (0.06) [3] Sedation 3 (0.57) [5] 3 ( 0.58) [3] 3 (0.17) [3] Vertigo 1 (0.20) [1] 1 (0.06) [1] Hallucination 1 (0.70) [1] – 1 (0.20) [1] 2 (0.11) [2] (auditory/visual) smoked marijuana day before

*source *n = number of subjects who reported an AE for a particular category; # is the number of individual reports.

4.3 Safety Profile

The Sponsor conducted several clinical studies to assess the safety of SHP465. These studies were conducted in adult (18-55), pediatric, and adolescent (6-17) populations. The subjects in these studies were randomly assigned to specific treatment groups and were blinded as to what they were given. There was one report of suicidal ideation in a pediatric clinical study; however, the person was on placebo and it was determined to not be the result of SHP465. The details of the AEs and instances of misuse are outlined in sections 4.2 and 4.4 of this review. The safety profile of SHP465 in regards to abuse were minimal when the drug was consumed as directed.

4.4 Evidence of Abuse, Misuse and Diversion in Clinical Trials

Compliance of drug use in phase 3 studies was determined by assessing the number of pills that an individual consumed between every visit to the clinic. Subjects were deemed to be compliant if they consumed between 80 and 120% of the pills they were instructed to consume in a specified period of Page 13 of 17

Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

time. In study SPD465-301, conducted in adult subjects, there were 4 (2.9%) subjects who were taking placebo that were noncompliant and 2 (1.5%) taking SHP465 that were noncompliant. In Study SPD465-303, there were 4 (3.8%) subjects in the placebo arm, and 6 (1.6%) subjects in the SPD465 arm that were regarded as noncompliant.

Importantly, subjects who were determined to use too much drug were present in both the pediatric and the adult clinical studies. In the pediatric population (study SHP465-305) there were 3 (2.3%) in the placebo group and 3 (2.3%) in the drug group who were determined to take over 120% of their drug. There were also pediatric subjects who were deemed noncompliant for not taking enough drug; 7 (5.34%) in the placebo group and 4 (3.0%) in the drug group. In another adult study SHP465-306 there were 2 (2.2%) subjects in the placebo group and 4 (2.2%) subjects in the drug group (12.5 and 37.5 mg) that were deemed to have taken more than 120% of their drug.

The number of subjects that discontinued various phase studies was 28 (5.19%) for those that received drug and 9 (1.67%) for those that received placebo. The majority of subjects were discontinued for AEs that were not related to abuse and that did not seem to be dose dependent. There was no association with abuse for any of the discontinued subjects.

Table 4 Subjects discontinued from phase 3 studies

Combined Phase 3 population study discontinuations/drop- outs* SHP465* PLACEBO N (%)N (%) TOTAL DISCONTINUED 28 5.19 9 1.67 Adverse Event 13 6.7 - - Lack of Efficacy - - 1 1.1 Lost to Follow-up 1 0.5 1 1.1 Protocol Violation - - 2 2.2 Withdrawal by Subject 9 4.5 3 3.4 Other 5 2.7 2 2.2 *source **address major dose differences

4.5 Tolerance and Physical Dependence Studies in Humans

The Sponsor did not conduct any tolerance or physical dependence clinical studies with SHP465. Cessation after chronic use of high doses of amphetamine have been shown to produce withdrawal like symptoms indicative of physical dependence. The withdrawal symptoms include: fatigue, vivid or unpleasant dreams, insomnia, agitation, and cravings. In a study that was used to validate the Amphetamine Cessation Symptom Assessment (ACSA), subjects reported using an average of 500 mg of amphetamine per day. Furthermore, the doses ranged from 100-6500 mg per day [11]. These doses are far above the highest therapeutic dose sought by the Sponsor of 50 mg/day. It is important to note, however, that this 50 mg dose would be the highest marketed amphetamine dose and could be sought after by individuals for abuse because of the larger amount of amphetamine in the product. Page 14 of 17

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Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

potential for abuse. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.

Signs and symptoms of (b) (4) amphetamine abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been seen. Abusers of (b) (4) amphetamine may (b) (4) use other unapproved routes of administration which can result in overdose and death [see Overdosage (10)].

To reduce the abuse of CNS stimulants, including MYDAYIS, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants, monitor for signs of abuse while on therapy, and re-evaluate the need for MYDAYIS use.

9.3Dependence

Tolerance

Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) may occur during the chronic therapy of CNS stimulants including MYDAYIS.

Dependence

III. REFERENCES

1. Heal, D.J., et al., Amphetamine, past and present--a pharmacological and clinical perspective. J Psychopharmacol, 2013. 27(6): p. 479-496.

2. Easton, N., et al., Differential effects of the D- and L- isomers of amphetamine on pharmacological MRI BOLD contrast in the rat. Psychopharmacology (Berl), 2007. 193(1): p. 11-30.

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Reference ID: 4110964 Mydayis [Mixed salts of a single entity amphetamine] [NDA 022063]

3. Easton, N., et al., Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology, 2007. 52(2): p. 405-14.

4. Riviere, G.J., W.B. Gentry, and S.M. Owens, Disposition of methamphetamine and its metabolite amphetamine in brain and other tissues in rats after intravenous administration. J Pharmacol Exp Ther, 2000. 292(3): p. 1042-1047.

5. Rasmussen, N., America's first amphetamine epidemic 1929-1971: a quantitative and qualitative retrospective with implications for the present. Am J Public Health, 2008. 98(6): p. 974-985.

6. Gosden, J., W.R. Buckett, and D.J. Heal, D-amphetamine-cued drug discrimination in rats: Predictive value for detecting stimulant drugs of abuse. British Journal of Pharmacology, 1996. 117: p. P169-P169.

7. de la Garza, R., C.E. Johanson, and C.R. Schuster, The discriminative stimulus properties of cocaine and d-amphetamine: a comparison of three routes of administration. NIDA Res Monogr, 1984. 49: p. 150-5.

8. Risner, M.E., Intravenous self-administration of d- and l-amphetamine by dog. Eur J Pharmacol, 1975. 32(02): p. 344-8.

9. Pharmacology and toxicology of amphetamine and related designer drugs. NIDA Res Monogr, 1989. 94: p. 1-357.

10. Griffith, J.D., J.G. Nutt, and D.R. Jasinski, A comparison of fenfluramine and amphetamine in man. Clin Pharmacol Ther, 1975. 18(5 Pt 1): p. 563-70.

11. McGregor, C., et al., Psychometric evaluation of the Amphetamine Cessation Symptom Assessment. J Subst Abuse Treat, 2008. 34(4): p. 443-9.

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Reference ID: 4110964 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------EDWARD G HAWKINS 06/13/2017

MARTIN S RUSINOWITZ 06/14/2017

SILVIA N CALDERON 06/14/2017

Reference ID: 4110964 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy

PATIENT LABELING REVIEW

Date: May 30, 2017

To: Mitchell Mathis, MD Director Division of Psychiatry Products (DPP)

Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP)

Barbara Fuller, RN, MSN, CWOCN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP)

Mathilda Fienkeng, PharmD, RAC Team Leader Office of Prescription Drug Promotion (OPDP)

From: Shawna Hutchins, MPH, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP)

Christine Bradshaw, PharmD Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Medication Guide (MG)

Drug Name (established MYDAYIS (mixed salts of a single-entity amphetamine name): product)

Dosage Form and Route: extended-release capsules, for oral use, CII Application NDA 022063 Type/Number: Applicant: Shire Development LLC

Reference ID: 4104602 1 INTRODUCTION On December 20, 2016, Shire Development LLC, resubmitted for the Agency’s review an original New Drug Application (NDA) for MYDAYIS (mixed salts of a single-entity amphetamine product) extended-release capsules, for oral use, CII, a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). This NDA was originally submitted on July 21, 2006, but received a Complete Response (CR) Letter issued by the Agency on May 17, 2007. This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Psychiatry Products (DPP) on January 23, 2017, for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for MYDAYIS (mixed salts of a single-entity amphetamine product) extended-release capsules, for oral use, CII.

2 MATERIAL REVIEWED x Draft MYDAYIS (mixed salts of a single-entity amphetamine product) MG received on December 20, 2016, and received by DMPP and OPDP on May 15, 2017. x Draft MYDAYIS (mixed salts of a single-entity amphetamine product) Prescribing Information (PI) received on December 20, 2016, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on May 15, 2017.

3 REVIEW METHODS In 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. In our collaborative review of the MG we: x simplified wording and clarified concepts where possible x ensured that the MG is consistent with the Prescribing Information (PI) x removed unnecessary or redundant information x ensured that the MG is free of promotional language or suggested revisions to ensure that it is free of promotional language x ensured that the MG meets the Regulations as specified in 21 CFR 208.20 x ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

Reference ID: 4104602 4 CONCLUSIONS The MG is acceptable with our recommended changes.

5 RECOMMENDATIONS x Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. x Our collaborative review of the MG is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the MG. Please let us know if you have any questions.

8 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

Reference ID: 4104602 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------SHAWNA L HUTCHINS 05/30/2017

CHRISTINE J BRADSHAW 05/30/2017

BARBARA A FULLER 05/30/2017

LASHAWN M GRIFFITHS 05/30/2017

Reference ID: 4104602 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information****

Memorandum

Date: May 26, 2017

To: Latrice Wilson, Regulatory Project Manager Division of Psychiatry Products (DPP)

From: Christine Bradshaw, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Through: Mathilda Fienkeng, Team Leader, OPDP

Subject: NDA 022063/O-1 OPDP labeling comments for MYDAYIS (mixed salts of a single- entity amphetamine product) extended-release capsules, for oral use, CII (Mydayis)

In response to DPP’s consult request dated January 23, 2017, OPDP has reviewed the draft product labeling (PI) and carton/container labeling for Mydayis.

OPDP’s comments on the draft PI for Mydayis are provided below, and are based on the substantially complete version of the PI provided via email by Latrice Wilson on May 15, 2017. Combined OPDP and Division of Medical Policy Programs (DMPP) comments on the proposed Medication Guide will be provided to DPP under separate cover.

Carton and Container Labeling

OPDP has reviewed the draft carton/container labeling submitted by the Sponsor on December 20, 2016, and downloaded from Global Submit on May 26, 2017.

OPDP notes that the formulation located on the label is listed as “ (b) (4) Release,” while the draft substantially complete version of the PI provided by DPP states, “Extended-Release.” OPDP recommends that the established name on the carton/container labeling be revised to be consistent with the PI. We defer to DPP.

If you have any questions, please feel free to contact me by phone at 301-796- 6796 or by email at [email protected]. OPDP appreciates the opportunity to provide comments on these materials. Thank you! 26 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

Reference ID: 4104308 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------CHRISTINE J BRADSHAW 05/26/2017

Reference ID: 4104308

LABEL AND LABELING REVIEW Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: May 18, 2017 Requesting Office or Division: Division of Psychiatry Products (DPP) Application Type and Number: NDA 022063 Product Name and Strength: Mydayis (Mixed Salts of a Single-Entity Amphetamine) (b) (4) release capsule 12.5 mg, 25 mg, 37.5 mg, 50 mg Product Type: Single-Ingredient Product Rx or OTC: Rx Applicant/Sponsor Name: Shire Development LLC Submission Date: December 20, 2016 OSE RCM #: 2017-125 DMEPA Primary Reviewer: Briana Rider, PharmD DMEPA Team Leader: Lolita White, PharmD

Reference ID: 4099942

1 REASON FOR REVIEW The Division of Psychiatry Products (DPP) requested this review as part of their evaluation of NDA 022063 Class 2 Resubmission for Mydayis (mixed salts of a single –entity amphetamine). DPP consulted DMEPA to specifically review the acceptability of the introduction of the Mydayis product to coexist with the similar mixed salt amphetamine product, Adderall XR. This review evaluates the proposed risk management plan (RMP), educational plan, container labels and prescribing information (PI) labeling for Mydayis (mixed salts of a single-entity amphetamine product) (b) (4) release capsulesa for areas of vulnerability that could lead to medication errors.

1.1 PRODUCT INFORMATION Mydayis is a central nervous system stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Mydayis is a once daily, triple-bead, single-entity mixed amphetamine salt (MAS) product for oral administration, and is comprised of sulfate salts of dextro- and levo-amphetamine, with dextroamphetamine saccharate and amphetamine asparate monohydrate. Mydayis consists of a triple bead product formulation. The first two beads provide a double-pulsed delivery of MAS, with the first bead immediately releasing MAS and the second bead providing a delayed release of MAS; these two beads are similar to the beads used in Adderall XR. The third bead is unique to the triple-bead Mydayis MAS formulation and provides an additional delayed-dose of MAS. The triple-bead, (b) (4) delivery extends the release of MAS for symptom coverage up to 16 hours post- administration and is intended to provide patients with ADHD with symptom control throughout the morning, afternoon, and evening hours following a single morning dose. Mydayis dosage should be individualized according to the therapeutic needs and response of the patient. Treatment should be initiated at 12.5 mg once daily upon awakening and titrated upward as needed at weekly increments of 12.5 mg up to a total daily dose of 50 mg for adults (18 to 55 years) and 25 mg for pediatric patients (b) (4) Mydayis may be taken whole or the capsule contents may be sprinkled over applesauce and consumed immediately. Mydayis is supplied a 12.5 mg, 25 mg, 37.5 mg, and 50 mg (b) (4) release capsules and packaged in bottles of 100. Mydayis should be dispensed in a tight, light-resistant container.

1.2 REGULATORY HISTORY Shire Development LLC submitted a 505(b)(1) NDA 022063 on July 21, 2006 for mixed salts of a single-entity amphetamine for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). An Approvable Letterb was issued to Shire on May 18, 2007, tentatively approving the

a The dosage form is currently under review by CMC/OPQ bLaughren, T. Approvable Letter for (b) (4) (mixed salts of a single entity amphetamine) NDA 022063, Silver Spring (MD): FDA, CDER, OSE, DMETS (US); 2007 MAY 24.

Reference ID: 4099942

We reviewed the proposed Prescribing Information (PI) labeling, container labels, educational plan, and risk management plan for risk of medication errors, including the robustness of the proposed approach to minimize the potential for medication errors involving confusion with Adderall XR (see Appendix A). Shire submitted a volunteered risk management plan (RMP) as part of their NDA 022066 Class 2 Resubmission for Mydayis (see Appendix F). The objectives of the RMP are to: 1. Ensure education regarding proper use of Mydayis and minimize nonmedical use and diversion by providing information to healthcare providers and patients/caregivers 2. Detect and evaluate potential signals of nonmedical use and diversion when and if they occur 3. Detect, if any, the contribution of Mydayis to the nonmedical use and diversion of prescription stimulants. The RMP includes two components: education and surveillance. The improvement and clarity of labels, labeling, medication guide, and packaging are among the tools that will be employed for education. Furthermore, upon approval of the NDA and throughout the lifecycle of the product, Shire intends to provide education by means of consumer and healthcare provider promotional activities and a professional education plan for healthcare providers with the following goals: a) Explain the concept of MAS formulations (slow versus intermediate release) b) Explain the unique formulation of Mydayis and how it differs from the currently marketed MAS formulations (e.g., ADDERALL and ADDERALL XR), including the differences in pharmacokinetic profiles and duration of symptom coverage c) Provide guidance to the appropriate use of Mydayis with regards to dosing In accordance with advice provided by the Agency at the April 25, 2014 Type C Written Responses Onlye meeting, Shire’s educational plan includes dissemination of information via the following venues: professional education programs, scientific publications and posters, branded promotional healthcare professional (HCP) assets (e.g., websites), Medical Science Liaison (MSL) materials for use in scientific discussions with HCPs, sales representatives promotional materials, consumer-directed educational and branded promotional assets (e.g., videos, consumer websites, patient brochures), digital channels, and social media in order to help minimize the potential for medication errors involving the inappropriate substitution of Mydayis for other amphetamine products on a milligram-per-milligram basis. Our review finds that the goals of the educational plan and the proposed implementation strategy are appropriate to address our previous concerns conveyed to the Sponsor in the May 18, 2007 Approvable Letter with regards to the overlap in product characteristics (i.e., 25 mg strength overlap, and identical established name and once daily administration) between Mydayis and Adderall XR. Therefore, we find the education plan component of the RMP acceptable.

e Patel, H. Type C WRO Final Meeting Minutes DARRTS 2014 APR 25.

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The second component of the Sponsor’s submitted RMP focuses on surveillance to detect and evaluate potential signals for nonmedical use, overdose and diversion. Our review finds routine surveillance to monitor postmarketing activities essential and appropriate for this product. We find the surveillance component of the RMP acceptable from a medication error perspective (e.g. overdose); however, we defer to the division for the appropriateness of the surveillance plan for nonmedical use and diversion. We previously evaluated whether the addition of a modifier to convey that the product is an extended-release dosage form will help to decrease confusion with Adderall XR as part of the review of the proposed proprietary name, Mydayis.f Our previous evaluation for the need of a modifier for Mydayis found that while a modifier may help to convey that both products are extended release formulations, a modifier will not convey the differences in the pharmacokinetic profiles, and thus, would be of limited utility in terms of differentiating the proposed product from Adderall XR. Therefore, in OSE Review #2017-12614118f, dated April 13, 2017, DMEPA found the proposed proprietary name, Mydayis, to be conditionally acceptable without the need for a modifier. We also considered the risk of confusion that may occur when the products are prescribed by their established names only, particularly if a generic equivalent becomes available. Since both Adderall XR and Mydayis have the same established name, both are administered once daily and both are extended release formulations, we find that the established name will not adequately differentiate the products. We find the optimization of container labels, PI labeling and implementation of the RPM will best ensure the safe and effective use of this product. Our review of the proposed Prescribing Information (PI) labeling and the container labels identified the following areas of needed improvement that may contribute to medication errors: 1. The Highlights of Prescribing Information and Full PI (FPI) can be revised to add and increase the prominence of critical information, regarding substitutability of similar products, to minimize the risk of medication error involving the inappropriate substitution of Mydayis for other amphetamine products on a milligram-per-milligram basis. 2. The current temperature statements within Section 16 How Supplied/Storage and Handling of the FPI and on the container label lack clarity. The statements do not contain the temperature scale designation (i.e., “°C” or “°F”) after each numerical value and pose risk of misinterpretation. 3. The (b) (4) color used to differentiate the 50 mg product strength (b) (4) for all the container labels and therefore does not afford adequate differentiation.

f Holmes, L. Proprietary Name Review for Mydayis (Mixed Salts of a Single-Entity Amphetamine Product) NDA 022063, Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2017 APR 13. RCM No.: 2017-12614118.

Reference ID: 4099942

4. The (b) (4) differentiate the product strengths on the container labels overlap with (b) (4) the existing Adderall XR container labels, which poses risk for medication error. 5. We note the presence of the following statement “ (b) (4) ” In accordance with 21 CFR 208.24(d), the label should also state how the Medication Guide is provided (e.g., enclosed, accompanying). 6. We note the presence of the following statement (b) (4) However, the container label does not bear a “usual dosage” statement in accordance with 21 CFR 201.55. Add a statement similar to the statement copied below to the side panel in accordance with 21 CFR 201.55. a. Usual Dose: One tablet once daily upon awakening. 7. The route of administration (b) (4) is present on the Principal Display Panel (PDP). However, the route of administration is not required and may contribute to clutter and hinder readability of important information. We provide recommendations regarding these areas below in Section 4.1 and 4.2 in order to help minimize the potential for medication errors to occur with use of the product. We also determined, that as presented, the container labels do not adequately convey to the end user that the product is not substitutable for other amphetamine products on a milligram- per-milligram basis. We are concerned that Mydayis may be inappropriately substituted for Adderall XR products since Mydayis and Adderall XR have the same established name, have an overlapping dose of 25 mg and are both dosed once daily. The most effective mechanism by which to differentiate the Mydayis and Adderall XR container labels is currently being evaluated and recommendations will be forthcoming under a separate cover.

4 CONCLUSION & RECOMMENDATIONS We conclude that Shire’s proposed RMP, educational plan, and implementation strategy are acceptable to mitigate risk of potential medication errors involving confusion with Adderall XR. We defer to the division on the acceptability of the proposed product surveillance plan to detect and evaluate potential signals for diversion, and nonmedical use. Our review of the labels and labeling identified areas that are vulnerable to medication error and we recommend revision to provide clarity, increase prominence of critical information and to ensure the safe use of the proposed product. We provide recommendations in Section 4.1 and 4.2 and recommend their implementation prior to approval of this NDA application.

4.1 RECOMMENDATIONS FOR THE DIVISION A. Highlights of Prescribing Information (HPI) 1. Dosage and Administration i. We note that a “non-substitutable” statement is present in Section 2.7 Switching from other Amphetamine Products in the Full Prescribing Information (FPI). However, this statement is absent from the HPI. We are concerned that Mydayis may be inappropriately substituted for other

Reference ID: 4099942

amphetamine products on a milligram-per-milligram basis. We recommend adding the same “non-substitutable” statement to the Dosage and Administration section of the HPI. B. Full Prescribing Information (FPI) 1. Section 16 – How Supplied/Storage and Handling i. The storage statements in Section 16.2 Storage and Handling do not contain the temperature scale designation (i.e., “°C” or “°F”) after each numerical value. As such, we are concerned that the acceptable storage temperature could be misinterpreted and pose risk of improper storage leading to decreased product quality. Ensure that the degree symbol and temperature scale follows each numeric value denoting temperature ranges. For example, revise “15-30°C (59 - 86°F)” to read “15°C - 30°C (59°F - 86°F)”.

4.2 RECOMMENDATIONS FOR SHIRE DEVELOPMENT LLC We recommend the following be implemented prior to approval of this NDA 022063: A. Container Labels, 12.5 mg, 25 mg, 37.5 mg, and 50 mg strengths 1. The (b) (4) color chosen to differentiate the 50 mg strength (b) (4) on all the container labels.(b) (4)

2. The storage statements do not contain the temperature scale designation (i.e., “°C” or “°F”) after each numerical value. As such, we are concerned that the acceptable storage temperature could be misinterpreted and pose risk of improper storage leading to decreased product quality. Ensure that the degree symbol and temperature scale follows each numeric value denoting temperature ranges. For example, revise “15-30°C (59 - 86°F)” to read “15°C - 30°C (59°F - 86°F)”. 3. We note that the presence of the following statement “Pharmacist: Medication Guide to be dispensed to patients.” In accordance with 21 CFR 208.24(d), the label should also state how the Medication Guide is provided (e.g., enclosed, accompanying) and these statements shall appear on the label in a prominent and conspicuous manner. Revise the statement in a manner such as displayed

Reference ID: 4099942

below to include how the Medication Guide will be provided and ensure that the statements appear on the label in a prominent and conspicuous manner: i. “Attention Pharmacist: Dispense the enclosed Medication Guide to each patient.” Or ii. “Attention Pharmacist: Dispense the accompanying Medication Guide to each patient.” 4. We note that the colors used to differentiate the 12 .5 mg(b) (4) and 50 mg (b) (4) strengths (b) (4) We are concerned that the overlapping strength color (b) (4) Revise the 12.5 mg and 50 mg Mydayis container labels to ensure the colors utilized to differentiate the strengths (b) (4) . 5. We note that a “usual dose” statement is missing from the container label. The following statement should be revised to comply with 21 CFR 201.55. Revise (b) (4) to read “Usual Dose: One tablet once daily upon awakening.” 6. The route of administration (b) (4) ” is present on the Principal Display Panel (PDP). The route of administration is only required per 21 CFR 201.100(b)(3) if the product is not for oral use. Remove the statement (b) (4) from the container label to minimize clutter and improve the readability of critical information.

Reference ID: 4099942

(b) (4) (b) (4)

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APPENDIX B. PREVIOUS DMEPA REVIEWS B.1 Methods On February 15, 2017, we searched the L:drive and AIMS using the terms, Mydayis AND Mixed Salts of a Single-Entity Amphetamine to identify reviews previously performed by DMEPA.

B.2 Results Our search identified two previous reviews.g,h In OSE Review 2006-303,g dated July 21, 2006, DMEPA (formerly DMETS - Division of Medication Errors and Technical Support) recommended that the Sponsor not introduce the product, especially with an overlapping strength of 25 mg with Adderall XR. It was recommended that the product labels and labeling (b) (4) should the product be approved and that Shire create and implement a plan for the education of healthcare professionals and consumers about the difference between the available Adderall formulations. Additional recommendations included: 1) relocating the net quantity statement away from the product strength, 2) relocating the CII symbol so the product strength immediately follows the established name, and 3) ensuring that the established name is at least half the size of the proprietary name. Recommendations for the insert labeling included removal of trailing zeros. In response to recommendations provided in OSE Review #2006-303, the Sponsor submitted revised container labels and insert labeling for review and comment. The revised labels and labeling were evaluated in OSE Review #2007-21.h The January 25, 2007 OSE Review notes that the CII symbol was relocated so the product strength immediately follows the established name but that the Sponsor failed to address the other safety concerns conveyed in OSE Review # 2006-303. In addition to the earlier recommendations, DMEPA (formerly DMETS) recommended (b) (4) the net quantity statement be revised so that it is not presented (b) (4) . DMEPA also recommended that the Sponsor include Section 17 (Patient Counseling Information) in the insert labeling since patients may need counseling on alternative administration of the product (i.e., sprinkle the entire contents on applesauce). We note that the Sponsor has addressed some of the safety concerns regarding the labels and labeling from our July 21, 2006 and January 25, 2007 reviews. However, some of our previous recommendations have not been implemented.

g Smith T. Label and Labeling Review for SPD 465 (Mixed Salts of a Single-Entity Amphetamine Product) NDA 022063, Silver Spring (MD): FDA, CDER, OSE, DMETS (US); 2006 JUL 21. RCM No.: 2006-303. h Wisniewski, L. Proprietary Name, Label, and Labeling Review for (b) (4) (Mixed Salts of a Single-Entity Amphetamine Product) NDA 022063, Silver Spring (MD): FDA, CDER, OSE, DMETS (US); 2007 JAN 25. RCM No.: 2007-21.

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APPENDIX F. RISK MANAGEMENT PLAN (RMP) AND EDUCATIONAL PLAN

Risk Management Plan Shire submitted a volunteered risk management plan (RMP) as part of their original NDA filing of NDA 022063 in 2007. According to Shire, the volunteered RMP was developed in the context of the benefits and risks of Mydayis with the goal of supporting realization of therapeutic benefits for the intended patient population while minimizing risks and unintended consequences to patients and others, by minimizing nonmedical use (misuse and abuse) and diversion. The original RMP was consistent with risk management activities in place at the time for other Shire prescription stimulants (i.e., Daytrana and Vyvanse).

Education Plan In the Approvable Letter issued to Shire on May 18, 2007, the Agency asked that Shire create and implement a plan for the education of healthcare professionals and consumers about the difference between their newly proposed formulation of mixed salts of a single-entity amphetamine and the available Adderall formulations. The Agency advised that advice from practicing healthcare providers should be sought on how to label and educate to adequately address the fact that the products are different despite having the same active ingredients, established name, dose, and dosing intervals. In the April 25, 2014 Type C Written Responses Only meeting, FDA agreed with Shire’s plan for educating healthcare providers about the difference between Adderall, Adderall XR and their newly proposed formulation of mixed salts of a single-entity amphetamine for the lifecycle of the product, but recommend that Shire also disseminate information via venues such as professional publications, healthcare websites, product representatives, etc.

F.2 Results Risk Management Plan A revised risk management plan (RMP) was provided in Module 1.16.1 of Shire’s December 20, 2016 Type 2 Resubmission of NDA 022063. According to Shire, the revised volunteered RMP reflects the results and conclusions of the completed risk management postmarketing surveillance for Daytrana and Vyvanse. The RMP consists of two components: education and surveillance.

Risk Management Plan.pdf

Reference ID: 4099942

Educational Plan The educational plan was provided in Module 1.11.1, Appendix 1 of Shire’s December 20, 2016 Type 2 Resubmission of NDA 022063.

Multiple Module Information Amendme

Reference ID: 4099942

APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed Using the principles of human factors and Failure Mode and Effects Analysis,i along with postmarket medication error data, we reviewed the following Mydayis labels and labeling submitted by Shire Development LLC on

x Container labels for Mydayis: submitted on December 20, 2016 x Prescribing Information: submitted on December 20, 2016 - no image x Container labels for Adderall XR: submitted in the last Annual Report dated December 9, 2016

G.2 Label and Labeling Images

5 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

i Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.

Reference ID: 4099942 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------BRIANA B RIDER 05/18/2017

LOLITA G WHITE 05/19/2017

Reference ID: 4099942

Page 2 Clinical Inspection Summary NDA 022063, Amphetamine (Mydayis)

This NDA class 2 resubmission dated 20 December 2016 was to address the deficiencies identified in the 18 May 2007 Approvable Letter and to respond to FDA’s request for a pediatric study in ADHD. It includes 2 new phase 3 clinical studies: 1) Protocol SHP465-305, a study in pediatric subjects aged 6-17 years inclusive with ADHD; 2) Protocol SHP465-306, a study conducted to explore lower doses of SHP465 and the dose response as treatment for ADHD.

Following are brief descriptions of these 2 studies. For detailed information, please refer to the background packages.

Protocol SHP465-305

Study subjects: 264 subjects were randomized Study sites: 36 sites in U.S.

Study Period: Study Initiation Date: 18 Jun 2015 Study Completion Date: 16 Feb 2016

This study was a 4-week randomized, double-blind, placebo-controlled study in which subjects aged 6-17 years inclusive with ADHD were randomized in equal numbers at baseline (Visit 2) to SHP465 or placebo to evaluate the efficacy and safety of SHP465. Subjects were titrated from a dose of 12.5 mg/day until an optimal dose was reached (up to a maximum dose of 25 mg/day); this dose was maintained during the dose-maintenance period.

The primary efficacy endpoint was the change from baseline of the ADHD Rating Scale-IV (ADHD-RS-IV) Total Score at Visit 6 (Week 4). The key secondary efficacy endpoint was the change from baseline of the Clinical Global Impression – Global Improvement (CGI-I) score.

According to the sponsor, SHP465 demonstrated statistically significant treatment effects in this population with ADHD compared with placebo on both the primary efficacy endpoint and the key secondary efficacy endpoint.

Protocol SHP465-306

Study subjects: 275 subjects were randomized Study sites: 43 sites in U.S.

Study Period: Study Initiation Date: 19 Nov 2015 Study Completion Date: 24 Mar 2016

This was a 4-week randomized, double-blind, placebo-controlled, parallel-group study that assessed the safety, tolerability, and treatment effect in adults aged 18-55 years who met DSM-V criteria for ADHD. The study had 4 periods: screening and washout; forced-dose titration; dose maintenance; and safety follow-up. Subjects were randomized in a 1:1:1 ratio, to two Mydayis treatment groups and a placebo group. Mydayis treatment group I received a dose of 12.5 mg/day throughout the study. Mydayis treatment group II was titrated on a weekly basis from the initial

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dose 12.5 mg until the target dose of 37.5 mg/day was reached by Week 3 and was maintained at 37.5 mg throughout the study (12.5 mg in Week 1, 25 mg in Week 2, and 37.5 mg in Weeks 3 and 4). The duration of the double-blind evaluation period (forced-dose titration and dose maintenance periods) was 4 weeks.

The primary endpoint was the change from baseline of the adult ADHD-RS-IV with Adult Prompts total score at Week 4. The key secondary efficacy endpoint was the change from baseline of the CGI-I score.

Selection of CI Inspections Dr. William Murphy has 22 INDs, had no prior CDER inspections, had high enrollment, and participated in both studies.

Dr. Michael Greenbaum has 39 INDs and had no prior CDER inspections, had high enrollment, and participated in both studies.

Dr. Valerie Arnold has 42 INDs, had high enrollment, and participated in both studies. Dr. Valerie Arnold has two prior CDER inspections: x 12-SEP-2005: VAI x 08-MAY-2007: NAI

Dr. Richard Weisler has 59 INDs and 4 prior CDER inspections: x 03-MAR-2003: VAI x 22-AUG-2007: VAI x 20-AUG-2009: OAI (inadequate drug accountability; failure to adhere to protocol and inadequate and inaccurate records) x 21-NOV-2011: NAI III. RESULTS (by site): Name of CI, Address, Site # Protocol # and Inspection Classification Subject # Date William R. Murphy, M.D. SHP465-305 3/15/2017 Preliminary 4601 W. 109th Street, Suite 208 13 randomized to classification: Overland Park, KS 66211 3/21/2017 NAI SHP465-305 (Site #2) SHP465-306 SHP465-306 (Site #101) 9 randomized Michael Greenbaum, M.D. SHP465-305 04/19/2017 Preliminary Capstone Clinical Research 7 randomized to classification: 1880 W. Winchester Road, Suite 204 04/26/2017 NAI Libertyville, IL 60048 SHP465-306 SHP465-305 (Site #9) 11 randomized SHP465-306 (Site #102)

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Name of CI, Address, Site # Protocol # and Inspection Classification Subject # Date Valerie Arnold, M.D. SHP465-305 3/13/2017 NAI Clinical Neuroscience Solution, INC 8 randomized to 6401 Poplar Avenue, Suite 420 3/15/2017 Memphis, TN 38119 SHP465-306 SHP465-305 (Site #13) 12 randomized SHP465-306 (Site #120) Richard H. Weisler, M.D. SHP465-306 01/30/2017 Preliminary PA & Associates 6 randomized to classification: 700 Spring Forest Rd., Suite 125 02/03/2017 NAI Raleigh, NC 27609 SHP465-306 (Site #137)

Key to Compliance Classifications NAI = No deviation from regulations. VAI = Deviation(s) from regulations. OAI = Significant deviations from regulations. Data unreliable

Preliminary classification: final classification pending. Preliminary classification based on information in 483 or preliminary communication with the field; EIR has not been received from the field, and complete review of EIR is pending. Final classification occurs when the post-inspectional letter has been sent to the inspected entity.

1. William R. Murphy, M.D. This site participated in both Studies SHP465-305and SHP465-306. In Study SHP465-305, 19 subjects were screened, 6 were considered screening failures, and 13 were enrolled. Among the 13 enrolled, 2 discontinued and 11 completed the study. In Study SHP465-306, 12 subjects were screened, 3 failed screening, and 9 were enrolled. Among the 9 enrolled, 1 discontinued and 8 completed the study. A complete review was conducted for all subjects for both studies.

The primary endpoint data were verified. There was no evidence of under-reporting of AEs, and no other regulatory deviations were identified at the site.

This clinical site appeared to be in compliance with Good Clinical Practices, and the data generated by this site appear acceptable in support of the respective indication.

2. Michael Greenbaum, M.D. This site participated in both Studies SHP465-305and SHP465-306. In Study SHP465-305, 7 subjects were screened and all were enrolled. Among all enrolled, one discontinued due to self-withdrawal as the subject was unable to swallow the medication and 6 completed the study. In Study SHP465-306, 14 subjects were screened, 3 failed the screening, and 11 were enrolled. All enrolled subjects completed the study. A complete review was conducted for all subjects enrolled in

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both studies.

The primary endpoint data were verified. There was no evidence of under-reporting of AEs and no other regulatory deviations were identified at the site.

This clinical site appeared to be in compliance with Good Clinical Practices, and the data generated by this site appear acceptable in support of the respective indication.

3. Valerie Arnold, M.D. This site participated in both SHP465-305and SHP465-306 studies. In Study SHP465-305, 12 subjects were screened, 4 were considered screening failure, and 8 were enrolled. All enrolled completed the study. In Study SHP465-306, 16 subjects were screened, 4 were considered screening failure, and 12 were enrolled. Among the 12 enrolled, 2 discontinued and 10 completed the study. A complete review was conducted for all subjects for both studies.

The primary endpoint data were verified. There was no evidence of under-reporting of AEs and no other regulatory deviations were identified at the site.

This clinical site appeared to be in compliance with Good Clinical Practices, and the data generated by this site appear acceptable in support of the respective indication.

4. Richard H. Weisler, M.D. This site participated in SHP465-306 study. In this study, 8 subjects were screened, 2 subjects were screen failures, and 6 subjects were enrolled. All enrolled subjects completed the study. A complete review of all subject records was conducted.

No significant regulatory violations were noted. The primary endpoint data were verified. There was no evidence of under-reporting of AEs.

This clinical site appeared to be in compliance with Good Clinical Practices, and the data generated by this site appear acceptable in support of the respective indication.

Reference ID: 4096878 Page 6 Clinical Inspection Summary NDA 022063, Amphetamine (Mydayis)

{See appended electronic signature page}

Jenn W. Sellers, M.D., PhD Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations CONCURRENCE: {See appended electronic signature page}

Susan Thompson, M.D. Team Leader, Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Kassa Ayalew, M.D., M.P.H Branch Chief Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

cc: Central Doc. Rm. NDA #022063 DPP/Division Director/ Mitchell Mathis DPP /Project Manager/Latrice Wilson DPP/Medical Officer/Nancy Dickinson DPP/ Clinical Team Leader/Javier Muniz OSI /Office Director/David Burrow OSI/DCCE/Division Director/Ni Khin OSI/DCCE/Branch Chief/Kassa Ayalew OSI/DCCE/Team Leader/Susan Thompson OSI/DCCE/GCP Reviewer/Jenn Sellers OSI/ GCP Program Analysts/Joseph Peacock/Yolanda Patague OSI/Database PM/Dana Walters

Reference ID: 4096878 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------JENN W SELLERS 05/11/2017

SUSAN D THOMPSON 05/11/2017

KASSA AYALEW 05/11/2017

Reference ID: 4096878