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DOCUMENT INFORMATION PAGE

This page is for FDA internal use only. Do NOT send this page with the letter. Application #(s): NDA 205831/S-005

Communication Type:

Communication Group:

Communication Name:

Communication ID:

Correspondence

1) sNDA Action 2) Postmarketing Requirement/Commitment 1) Approval 2) PMR/PMC Fulfilled 1) COR-SNDAACTION-05 2) COR-PMRPMC-08

Drafted by:

Clearance History

by:

Finalized:

Filename:

Signatory Authority:

Use Statement: Notes:

For Efficacy Supplements or Labeling Supplements: OND Division Director or Deputy Division Director. Person who is covering for the signatory authority can sign on their behalf (i.e., the signature block on the letter will not change) For CMC Supplements with Labeling: OPQ Division Director or Branch Chief Use to notify applicant of an approval action for a supplemental application that includes changes to the label(s) and/or labeling USE "sNDA Approval [OTC ONLY]" template for Over-theCounter sNDA Approvals USE COR-SNDAACTION-06 FOR sNDA CMC APPROVALS USE COR-SNDAACTION-09 FOR sNDA TENTATIVE APPROVALS

If supplement approval also fulfills a PMR/PMC, this letter will need to be double-coded as PMR-PMC Fulfilled.

Note: Remember to check for acceptability of facility prior to issuing approval letter.

Labeling: Before attaching labeling, ensure that the following items have been addressed (see "Final Check of Labeling Format Before Attaching Documents to Approval Letter" slide presentation on LDT's intranet site for details):

Reference ID: 4449063

1) Remove annotations (e.g., tracked changes, comments, content in headers/footers); however, page numbers are allowed (see #5)

2) Remove line numbers 3) Assess number of columns in three sections of labeling (two

columns for Highlights and Table of Contents, and onecolumn for Full Prescribing Information). If incorrect, ask applicant to address. 4) Correct/update dates in Highlights (e.g., Initial U.S. Approval, Recent Major Changes, and Revision Date) 5) If page numbers are included, ensure first page of each labeling document starts with Page #1 (e.g. Prescribing Information, Patient Package Insert, Medication Guide, and Instructions for Use all start with Page #1) Version: 05/21/2019 END OF DOCUMENT INFORMATION PAGE The letter begins on the next page.

Reference ID: 4449063

NDA 205831/S-005

SUPPLEMENT APPROVAL/ FULFILLMENT OF POSTMARKETING REQUIREMENTS

Rhodes Pharmaceuticals L.P. Attention: Todd M. Delehant, PhD Director Regulatory Affairs 498 Washington Street Coventry, RI 02816

Dear Dr. Delehant:

Please refer to your Supplemental New Drug Application (sNDA) dated September 14, 2018, received September 14, 2018 submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Aptensio XR (methylphenidate hydrochloride extended-release) capsules 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg.

We acknowledge receipt of your major amendment dated March 14, 2019, which extended the goal date by three months.

This Prior Approval supplemental new drug application provides for the addition of safety information in pediatric patients ages four to less than 6 with Attention Deficit Hyperactivity Disorder (ADHD).

APPROVAL & LABELING

We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling.

WAIVER OF ? PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS

Please note that we have previously granted a waiver of the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of Prescribing Information.

Reference ID: 4449063

NDA 205831/S-005 Page 2

CONTENT OF LABELING

As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at .1 Content of labeling must be identical to the enclosed labeling (text for the Prescribing Information, and Medication Guide), with the addition of any labeling changes in pending "Changes Being Effected" (CBE) supplements, as well as annual reportable changes not included in the enclosed labeling.

Information on submitting SPL files using eList may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As.2

The SPL will be accessible from publicly available labeling repositories.

Also within 14 days, amend all pending supplemental applications that include labeling changes for this NDA, including CBE supplements for which FDA has not yet issued an action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word format, that includes the changes approved in this supplemental application, as well as annual reportable changes. To facilitate review of your submission(s), provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy should provide appropriate annotations, including supplement number(s) and annual report date(s).

REQUIRED PEDIATRIC ASSESSMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.

This product is appropriately labeled for use in all relevant pediatric populations. Therefore, no additional pediatric studies are needed at this time.

1 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance Documents Database .

U.S. Food and Drug Administration Silver Spring, MD 20993

Reference ID: 4449063

NDA 205831/S-005 Page 3

FULFILLMENT OF POSTMARKETING REQUIREMENTS

We have received your submissions dated April 11, 2018, and September 14, 2018, containing the final reports for the following postmarketing requirements listed in the April 17, 2015, approval letter.

2899-1 2899-2 2899-3

A randomized, double-blind, placebo-controlled, flexible-dose titration study of methylphenidate hydrochloride extended-release capsules (Aptensio XR) in children ages 4 to 5 years diagnosed with ADHD. A single-dose, open-label, randomized pharmacokinetic study of Aptensio XR capsules in male or female children (4 to less than 6 years of age) with ADHD in fed condition. A one year Pediatric Open-Label Safety Study for patients age 4 to 5 years (at the time of entry into Study 1 or Study 2 or at the time of enrollment if directly enrolled into Study 3) with ADHD.

We have reviewed your submissions and conclude that the above requirements were fulfilled.

This completes all of your postmarketing requirements acknowledged in our April 17, 2015, letter.

PROMOTIONAL MATERIALS

You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory comments, (2) the proposed materials in draft or mock-up form with annotated references, and (3) the Prescribing Information to:

OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion (OPDP) 5901-B Ammendale Road Beltsville, MD 20705-1266

Alternatively, you may submit a request for advisory comments electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft guidance for industry Providing Regulatory Submissions in Electronic and Non-Electronic Format-Promotional Labeling and Advertising Materials for Human Prescription Drugs.3

3 When final, this guidance will represent the FDA's current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at .

U.S. Food and Drug Administration Silver Spring, MD 20993

Reference ID: 4449063

NDA 205831/S-005 Page 4

You must submit final promotional materials and Prescribing Information, accompanied by a Form FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at .4 Information and Instructions for completing the form can be found at .5 For more information about submission of promotional materials to the Office of Prescription Drug Promotion (OPDP), see .6 REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). If you have any questions, call Shin-Ye Sandy Chang, at (301) 796-3971, or email shinye.chang@fda..

Sincerely, {See appended electronic signature page} Tiffany R. Farchione MD Acting Director Division of Psychiatry Products Office of Drug Evaluation I Center for Drug Evaluation and Research

ENCLOSURES: ? Content of Labeling o Prescribing Information o Medication Guide

4 5 6 U.S. Food and Drug Administration Silver Spring, MD 20993

Reference ID: 4449063

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use APTENSIO XR? safely and effectively. See full prescribing information for APTENSIO XR

APTENSIO XR? (methylphenidate hydrochloride extended-release) capsules, for oral use, CII Initial U.S. Approval: 1955

WARNING: ABUSE AND DEPENDENCE

See full prescribing information for complete boxed warning.

? CNS stimulants, including APTENSIO XR, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. (5.1, 9.2, 9.3)

? Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. (5.1, 9.2, 9.3)

`

---------------------------RECENT MAJOR CHANGES--------------------------

Indications and Usage (1)

06/2019

Warnings and Precautions (5.7)

06/2019

----------------------------INDICATIONS AND USAGE-------------------------- APTENSIO XR is a central nervous system (CNS) stimulant indicated for the

treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6

years and older. (1)

Limitations of Use:

Pediatric patients younger than 6 years of age experienced higher plasma

exposure than patients 6 years and older at the same dose and high rates of

adverse reactions, most notably weight loss. (8.4)

--------------------DOSAGE AND ADMINISTRATION------------------------ ? Recommended starting dose for patients 6 years and older: 10 mg once daily

with or without food in the morning. Dosage may be increased weekly in increments of 10 mg per day. Daily dosage above 60 mg is not recommended. (2.1) ? Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce. (2.1)

-----------------DOSAGE FORMS AND STRENGTHS----------------------- Extended-Release Capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 60 mg of methylphenidate hydrochloride, which is equivalent to 8.6 mg, 13.0 mg, 17.3 mg, 25.9 mg, 34.6 mg, 43.2 mg, and 51.9 mg of methylphenidate free base, respectively, per capsule. (3)

--------------------------CONTRAINDICATIONS--------------------------------- ? Known hypersensitivity to methylphenidate or product components. (4) ? Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of

an MAOI within the preceding 14 days. (4)

-------------------WARNINGS AND PRECAUTIONS-------------------------- ? Serious Cardiovascular Events: Sudden death has been reported in

association with CNS stimulant treatment at recommended doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmias, or coronary artery disease. (5.2) ? Blood Pressure and Heart Rate Increases: Monitor blood pressure and

pulse. Consider the benefits and risks in patients for whom an increase in

blood pressure or heart rate would be problematic. (5.3)

? Psychiatric Adverse Reactions: Use of stimulants may cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychiatric illness. Evaluate for bipolar disorder prior to APTENSIO XR use. (5.4) ? Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed. (5.5) ? Peripheral Vasculopathy, including Raynaud's Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants. (5.6) ? Long-Term Suppression of Growth: Monitor height and weight at

appropriate intervals in pediatric patients. (5.7)

------------------------------ADVERSE REACTIONS--------------------------- The most common adverse reactions in double-blind clinical trials (> 5% and twice the rate of placebo) in pediatric patients 6 to 17 years were abdominal pain, decreased appetite, headache and insomnia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals L.P. at (1-888-827-0616); or FDA at 1-800-FDA-1088 or medwatch

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 06/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ABUSE AND DEPENDENCE 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

2.1 Pretreatment Screening 2.2 General Dosing Information 2.3 Dose Reduction and Discontinuation to 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Potential for Abuse and Dependence 5.2 Serious Cardiovascular Events 5.3 Blood Pressure and Heart Rate Increases 5.4 Psychiatric Adverse Reactions 5.5 Priapism 5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon 5.7 Long-Term Suppression of Growth 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience

6.2Post-Marketing Experience

7 DRUG INTERACTIONS 7.1 Clinically Important Interactions with APTENSIO XR 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation

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8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Signs and Symptoms 10.2 Management of Overdose 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of

Fertility

14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: ABUSE AND DEPENDENCE CNS stimulants, including APTENSIO XR, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Warning and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].

1 INDICATIONS AND USAGE

APTENSIO XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14)]. Limitations of Use Pediatric patients younger than 6 years of age experienced higher plasma exposure than patients 6 years and older at the same dose and high rates of adverse reactions, most notably weight loss [see Use in Specific Populations (8.4)].

2 DOSAGE AND ADMINISTRATION 2.1 Pretreatment Screening Prior to treating pediatric patients and adults with CNS stimulants including APTENSIO XR, assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions 5.2]. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re evaluate the need for APTENSIO XR use [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)]. 2.2 General Dosing Information The recommended starting dose of APTENSIO XR for patients 6 years and older is 10 mg once daily in the morning with or without food. Advise patients to establish a routine pattern with regard to meals. The dose should be individualized according to the needs and response of the patient. The dose may be titrated weekly in increments of 10 mg. Daily doses above 60 mg have not been studied and are not recommended. APTENSIO XR may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day. Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re evaluate the long-term use of APTENSIO XR, and adjust dosage as needed. 2.3 Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur; the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

3 DOSAGE FORMS AND STRENGTHS ? 10 mg Extended-Release Capsules ? light turquoise blue cap/white body

Reference ID: 4449063

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