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REMS in the Community Pharmacy 1

Objectives 2

By completing the lesson, the pharmacist will be able to: 3

Discuss the history of the REMS program 4

Describe the elements of the REMS program 5

Identify when a REMS might be used for a particular drug 6

Identify REMS elements employed with medications dispensed in community pharmacy 7

Discuss selection provision in Ohio law related to REMS requirements 8 9

Introduction 10

Federal law requires prescription drugs to be safe and effective. Clinical trials and testing before 11

a drug’s labelling is approved involves significant time and expense. What happens after a 12 drug’s labelling is approved? Post-marketing surveillance plays a more significant role than ever 13 in assuring each drug is used in a manner considered to be safe and effective. FDA’s current 14

post-marketing effort is referred to as Risk Evaluation and Mitigation Strategies (REMS). 15 16

This program will outline the REMS elements and show them in use with medications 17 commonly dispensed in community pharmacy settings. The discussion will focus on: 18

Accutane 19

Testosterone (topical) e.g. Androgel, Axiron 20

Chantix 21

Suboxone 22

23 In addition to REMS, this lesson will discuss: 24

OAC 4729-5-18 Patient Profiles 25

OAC 4729-5-20 Prospective Drug Utilization Review 26

OAC 4729-5-21 Manner of Processing a Prescription (legitimate medical purpose) 27

OAC 4729-5-22 Patient Counseling 28

29 History of REMS 30

In 2007, a new law that gave FDA many new authorities and responsibilities to enhance drug 31

safety was enacted. The Food and Drug Administration Amendments Act (FDAAA) and one of 32 its provisions gave FDA the authority to require a REMS from manufacturers to help ensure that 33

the benefits of a drug or biological product outweigh its risks. 34 35 Other, similar and less formal mechanisms were already in place. For example, in 1989 FDA 36

and Hoffman-LaRoche established the well-known system for monitoring the use of Accutane in 37 woman of child-bearing age. See www.ipledgeprogram.com. In 2005, FDA also created a risk 38

management system called Risk Minimization Action Plan (RiskMAP). A few drugs were 39 selected for RiskMAP monitoring, including: 40

Clozaril® Patient Management System 41

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Thalidomide (Thalomid ®) STEPS program (System for Thalidomide Education and 1

Prescribing Safety) 2

Isotretinoin (Accutane ®) iPLEDGE program 3

Dofetilide (Tikosyn ®) T.I.P.S. 4

5 Some regulators felt that a more structured system was needed to decide when and whether ALL 6

medications might be subject to more stringent post-marketing surveillance requirements. This 7 provided the impetus for REMS. See 21 U.S. Code §355.1. 8

9 General Overview of REMS 10

Not all drugs require a REMS. Some drugs are so toxic that the small amount of benefits 11 provided are insufficient to permit distribution, even when some patients would benefit from use. 12 Likewise, some drugs are very effective and have relatively few or minor toxicities or secondary 13

effects. It is those chemical entities “in between” where REMS comes into play. The FDA 14 views some drugs as being effective enough to be prescribed, provided certain mandatory 15

strategies or elements are in effect to monitor use. 16 17 FDA is required to consider the following factors in deciding whether to require a REMS: 18

estimated size of the population likely to use the drug involved 19

seriousness of the disease or condition that is to be treated with the drug 20

expected benefit of the drug with respect to such disease or condition 21

expected or actual duration of treatment with the drug 22

seriousness of any known or potential adverse events that may be related to the drug and 23 the background incidence of such events in the population likely to use the drug 24

whether the drug is a new molecular entity 25 See 21 U.S. Code §355.1(a)(1). 26

27 The four elements that may be included in any REMS, each discussed herein, are: 28

Medication Guide 29

Communication Plan 30

Elements To Assure Safe Use 31

Implementation System 32

33 A REMS may be required by the FDA as part of the approval of a new product, or for an 34

approved product when new safety information arises. For purposes of consistency, the REMS 35

follow a standard template. See Guidance for Industry Format and Content of Proposed Risk 36

Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS 37

Modifications at: 38

www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm1841239

8.pdf. Last accessed September 11, 2015. It is of interest to note that foreign-language versions 40

of REMS elements, such as Medication Guides, patient package inserts, communication and 41

education materials, enrollment forms, prescriber and patient agreements, and others, are not 42

considered part of the approved REMS. FDA will not review foreign- language versions of 43

REMS. 44

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Medication Guide 1

Since 1998, FDA had the authority to require distribution of medication guides. See 21 CFR 2

208.20. [63 FR 66396, Dec. 1, 1998, as amended at 73 FR 404, Jan. 3, 2008.] FDA can require 3

the development of, or changes to, a medication guide and can require these to be completed 4

quickly, whether or not a medication guide is part of a REMS. Medication guides are part of 5

labeling (21 CFR 201.57(c)) and are subject to the safety labeling change provisions of section 6

505(o)(4) of the FD&C Act, added by FDAAA. 7

Where required, a medication guide must be provided to the patient or the patient’s agent in the 8

following four situations: 9

1. When the patient or the patient’s agent requests a medication guide. 10

2. When a drug is dispensed in an outpatient setting (e.g., retail pharmacy, hospital 11

ambulatory care pharmacy) and the product will then be used by the patient without 12

direct supervision by a healthcare professional. 13

3. The first time a drug is dispensed to a healthcare professional for administration to a 14

patient in an outpatient setting, such as in a clinic or dialysis or infusion center. 15

4. The first time a drug is dispensed in an outpatient setting of any kind, after a Medication 16

Guide is materially changed (e.g., after addition of a new indication, new safety 17

information). FDA will provide notice when this occurs. 18

The two most common instances where a medication guide is not required are: 19

for inpatients, unless the patient requests one 20

for outpatients refills when the drug is dispensed to a healthcare professional for 21

administration to a patient, such as in a clinic or dialysis or infusion center 22 23 For the typical community pharmacist, the medication guide is required for each dispensing of 24

the drug. Of course, when the patient is discharged from the hospital or inpatient setting with a 25

new prescription for administration at home, the appropriate medication guide(s) should be 26

provided when the outpatient prescription is dispensed. The manufacturer of a drug product for 27

which a medication guide is required must obtain FDA approval of the medication guide before 28

the medication guide may be distributed. See 21 CFR 208.24 29

Communication Plan 30

When REMS requires a Communication Plan, the information will be directed to one of more 31

members of the healthcare team or drug distribution chain. For example, prescribers may be sent 32

written material to review. Also, prescribers may be sent material to review in person with each 33

patient – a sort of checklist to make sure patients understand proper use, monitoring, laboratory 34

testing, record keeping, and the like. In such a case, documenting review by both patient and 35

prescriber together is employed. These materials will be available on both the FDA.gov website 36

and websites provided by the manufacturers. The isotretinoin REMS includes a number of 37

letters and communications, as discussed in the examples below. 38

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Elements To Assure Safe Use 1

FDA believes that sometimes, providing information alone is not enough. In such cases, 2 additional Elements To Assure Safe Use (ETASU) will be required. ETASU are essentially 3 mechanisms to restrict distribution of the drug. Requiring that patients not only receive 4

information but formally “enroll” in a monitoring program may be required. Similarly, 5 prescribers and pharmacists may face similar enrollment requirements. Mandatory laboratory 6

testing may be required. Requiring that certain “certification stickers” are placed on written 7 prescriptions is another mechanism to document compliance with an ETASU program. As a 8 related aside, some third party payers may audit and refuse to pay for prescriptions not showing 9

these stickers. The REMS for Suboxone includes a number of ETASU, as discussed in the 10 examples below. 11

12 The first drug with an ETASU under the REMS program was Entereg, used to treat disruption of 13 normal motor activity of the gastrointestinal tract after surgery. The REMS for Entereg limited 14

its dispensing to short-term use (no more than fifteen 15 doses for seven days) only for inpatients 15 of certified hospitals. The REMS for Entereg served as a sort of prototype for subsequent 16 approvals of high risk products that were felt to need an element to ensure safe use. 17

18 Implementation System 19

FDA may require the implementation system to include a description of how applicable products 20 will be distributed. In addition, as part of the implementation system, FDA may require the 21

certification of wholesalers and/or distributors to ensure the product is distributed only to 22 certified or otherwise specified pharmacies, practitioners, or healthcare settings that dispense the 23 drug, or only to patients who meet the requirements of the REMS. The implementation system 24

may include: 25

a description of how the drug will be distributed 26

certification of wholesalers and distributors 27

a database of all entities certified to use the drug 28

periodic audits of those certified entities 29 30

Each REMS requires ongoing assessment by the manufacturer and FDA review. The standard 31 timetable for submission of assessments is: 32

eighteen (18) months after the REMS is approved 33

three (3) years after the REMS is approved 34

seven (7) years year after the REMS is approved 35 36

The manufacture can also submit a voluntary REMS assessment at any time. The REMS 37 assessment must also provide the status of all studies the manufacturer is conducting as well as 38 any difficulties that have been encountered. 39

40 REMS and Selected Outpatient Medications 41

The FDA website has a wealth of information available for the REMS program. As of the time 42 of this writing, there are eighty-four (84) medications active in the REMS program, with a 43 history of two-hundred forty-four (244) listings since its beginning. The common community 44

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pharmacy based medications listed in this lesson include a brief synopsis of materials available 1 from FDA at http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm. 2

3 Isotretinoin (Accutane) 4

Medication Guide – patient education guide (male and female versions), activation form, consent 5 form, pharmacist guide, Website: www.ipledgeprogram.com and toll-free number 1-866-495-6 0654, available Monday to Saturday, 9 AM - 12 AM (Midnight) ET. The medication guide must 7

be provided with each prescription or when requested by the patient. 8

Prescribers must register and enter required information (pregnancy test results, 2 forms of 9

contraception used, confirmation of patient counseling) in the iPLEDGE system for patients 10 to be qualified to receive a prescription. Prescribers must document that all patients meet the 11

requirements in the iPLEDGE program. 12

Only patients who are registered by prescribers in the iPLEDGE program can receive 13 isotretinoin. 14

Female patients of childbearing potential must enter required information (2 forms of 15 contraception used, answer questions on program requirements) in the iPLEDGE system in 16

order to be qualified to receive a prescription. 17

Only pharmacies registered with and activated in the iPLEDGE program can dispense 18

isotretinoin. Pharmacists must access the iPLEDGE system to receive authorization to fill 19 and dispense every isotretinoin prescription. 20

Manufacturers will only ship isotretinoin to iPLEDGE-registered entities (e.g., direct vendor 21 pharmacies, wholesalers). 22

Wholesalers must register annually in the iPLEDGE program. A registered wholesaler may 23 distribute only FDA-approved isotretinoin products. 24

25

Testosterone topical (Androgel) 26 Medication Guide only. The medication guide must be provided with each prescription or when 27

requested by the patient. Highlights include: 28

Women and children should avoid contact with the unwashed or unclothed area where 29

ANDROGEL has been applied to the skin. 30

ANDROGEL is to be applied to the area of the shoulders and upper arms that will be covered 31

by a short sleeve t-shirt. Do not apply ANDROGEL to any other parts of the body such as 32 your penis or scrotum. 33

To lower the risk of transfer of ANDROGEL to others: 34

o Wash hands right away with soap and water after applying ANDROGEL 35 o After the gel has dried, cover the application area with clothing. Keep the area 36

covered until washing the application area well or showering. 37 38 Chantix 39

Medication Guide only. The medication guide must be provided with each prescription or when 40 requested by the patient. See http://www.chantix.com/. Highlights include: 41

Stop taking CHANTIX and call prescriber right away with reports of agitation, hostility, 42 depression or changes in behavior or thinking, or with any of the following symptoms: 43

thoughts about suicide or dying, or attempts to commit suicide 44

new or worse depression, anxiety, or panic attacks 45

acting aggressive, being angry, or violent 46

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an extreme increase in activity and talking (mania) 1

seeing or hearing things that are not there (hallucinations) 2

feeling people are against you (paranoia) 3

4 Suboxone 5 Medication Guide: www.SuboxoneFilmREMS.com or call 1‐877‐SUBOXONE (1‐877‐782‐6

6966). The medication guide must be provided with each prescription or when requested by the 7

patient. 8 Elements to Assure Safe Use: SUBOXONE sublingual film will only be dispensed by the 9 prescriber or prescribed to patients with documentation of the following safe use conditions: 10

Verification that the patient meets the diagnostic criteria for opioid dependence 11

Risks described in the professional labeling and the Medication Guide have been 12

discussed with the patient 13

Safe storage of the medication has been explained and reviewed with the patient 14

After appropriate induction, the patient is prescribed a limited amount of medication at 15 the first visit 16

17 Pharmacy: To further reinforce safe use conditions, manufacturer will ensure that within 30 days 18

of FDA approval of the SUBOXONE sublingual film REMS, a “Dear Pharmacist Letter” will be 19 mailed to all pharmacists on a national mailing list of all retail pharmacies authorized by DEA to 20 handle schedule 3 controlled substances on a national mailing list from the National Technical 21

Information Service. The pharmacist brochure, “Office‐Based Buprenorphine Therapy for 22

Opioid Dependence: Important Information for Pharmacists” will be appended to the “Dear 23 Pharmacist Letter.” 24 Monitoring 25

Each patient using SUBOXONE sublingual film will be subject to the following monitoring: 26

Return visits are scheduled at intervals commensurate with patient stability. Weekly, or 27

more frequent, visits are recommended for the first month. 28

Assessment and reinforcement of patient’s compliance with the prescribed medication. 29

Assessment of appropriateness of dosage prescribed. 30

Assessment of whether patient is receiving the necessary psychosocial support. 31

Assessment of whether patient is making adequate progress towards treatment goals. 32 Implementation System - Manufacturer will monitor compliance with the requirements to 33

document prescribing and dispensing with documentation of safe use conditions through surveys 34 of patients and prescribers, evaluations of health care utilization databases, and ongoing 35 surveillance. 36

37 Ohio Law Provisions 38

Ohio law requires that all medication dispensing meet guideline to assure proper medication use. 39 The following four rules are particularly important to keep in mind: 40

OAC 4729-5-18 Patient Profiles 41

OAC 4729-5-20 Prospective Drug Utilization Review 42

OAC 4729-5-21 Manner of Processing a Prescription (legitimate medical purpose) 43

OAC 4729-5-22 Patient Counseling 44

45

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Patient profiles must include a “history of or active chronic conditions or disease states.” See 1 OAC 4729-5-18 (A) (1) (h). While these disease states may sometimes be inferred from the 2

medications themselves, it is best to update these conditions frequently. Mental health 3 conditions are particularly important for the pharmacist to know of for patients receiving 4

testosterone, Chantix, and Suboxone. Pharmacists should also be mindful of the need for 5 monitoring of birth control when isotretinoin is dispensed. 6 7

OAC 4729-5-20, Prospective drug utilization review, directs the pharmacist to review all 8 prescriptions, both new and refills, prior to dispensing. Regarding the medications discussed 9

already, compliance to therapy is particularly important for medications treating addiction issues 10 such as Chantix and Suboxone. 11 12

OAC 4729-5-22 discusses patient counseling. Due to the nature of REMS drugs, additional and 13 potentially more specific, detailed counseling may be appropriate for patients receiving these 14

particular medications. The FDA website and the website for each REMS medication include 15 detailed materials which may be of value to include during the patient's counseling discussion. 16 17

All prescriptions must be issued for a legitimate medical purpose in the usual course of 18 professional practice by the prescriber: See OAC 4729-5-21 (A) and 4729-5-30 (A). Some 19

REMS require substantial documentation in order for the prescription to be considered legitimate 20 and the medication to be supplied to the patient. One such medication is Thalomid. For each 21 prescription, the prescriber must obtain a unique prescription authorization number and 22

document that number on the prescription. This unique prescription authorization number is 23 required for each prescription to be legitimate. The pharmacist needs to obtain a confirmation 24

number in order to fill the prescription. Both of these numbers must be provided on the 25 prescription when dispensing. 26 27

In addition, a legitimate prescription may allow no more than a 28 day supply – with no refills. 28 Further, to reduce the prospects of stockpiling, the pharmacist should dispense each new 29

prescription only if there are seven (7) days or less remaining on the existing prescription. The 30 Thalomid REMS employs a restricted distribution program through enrolled specialty 31 pharmacies. Medication is shipped from one of these enrolled pharmacies to the patient. The 32

FDA and Celgene also provide an Education and Counseling Checklist for Pharmacies. 33 Information about THALOMID and the THALOMID REMS™ program can be obtained by 34

calling the Celgene Customer Care Center toll-free at 1-888-423-5436, or at 35 www.CelgeneRiskManagement.com. A list of network pharmacies can be obtained at 36 http://www.celgene.com/patients/rems-pharmacy-network/. There are currently twenty nine (29) 37

pharmacies in the network. 38 39

In addition to the medications discussion in this lesson, the following other common medications 40 have REMS the pharmacist may want to review: 41

Mycophenolate [CELLCEPT] 42

Rosiglitazone [AVANDIA] 43

Buproprion [ZYBAN] 44

45

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Take Away Points 1

Know your patient and history. The medication guide is the most common REMS 2

element the community pharmacist will encounter. 3

Inpatient distribution of the medication guide is generally limited to requests for 4

information by the patient. 5

Update and review the patient profile and patient history each time before dispensing. 6

Look for potential excessively early refills and duplications of therapy. 7

Many REMS considerations are directed to psychiatric disorders and symptoms, 8

requiring the pharmacist to deal with these sensitive subjects. 9

Manufacturers and wholesalers may have their own independent REMS requirements in 10

addition to those of the pharmacist and pharmacy. 11

Isotretinoin dispensing requires extensive intervention at each dispensing. 12

REMS medications and requirements are updated frequently – refer to REMS website 13 frequently. http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm 14

Many dispensing errors can be avoided and detected while the pharmacist is reviewing 15 proper use of medication with a patient – another reason to counsel. 16

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Questions – choose the one most correct answer. A passing score is seventy percent. 1 1. The pharmacist must determine the legitimate medical need for which of the following 2

before dispensing them to a patient. 3 a. Suboxone 4

b. Testosterone topical products 5 c. Chantix 6 d. all of the above 7

2. Providing the REMS medication guide is optional for community pharmacists dispensing 8

Chantix. 9 a. true 10

b. false 11 3. Which of the following is the most commonly used REMS element: 12

a. Medication Guide 13 b. ETASU 14 c. Implementation system 15 d. Communication plan 16

4. The standard timetable for FDA to review a manufacturer’s assessments of each REMS 17 includes: 18

a. eighteen (18) months after the REMS is approved 19 b. three (3) years after the REMS is approved 20 c. seven (7) years year after the REMS is approved 21 d. all of the above 22

5. The REMS for Chantix provides the patient stop taking Chantix and call the prescriber 23 right away with reports of: 24

a. Agitation 25 b. Dry mouth 26 c. Feelings of indigestion 27 d. All of the above 28

6. The REMS for topical testosterone gel provides the patient do all of the following 29 except: 30

a. Avoid exposure of women and children to the medication 31 b. Apply the medication to the scrotum 32 c. Wash hands after application of the medication 33 d. Cover the application area with clothing after the gel has dried 34

7. The REMS for Suboxone involves which of the following parties: 35 a. The pharmacist 36 b. The wholesaler 37

c. The prescriber 38 d. All of the above 39

8. Which of the following drugs was the first to employ an ETASU under the REMS 40

program: 41 a. Suboxone 42 b. Entereg 43

c. Chantix 44 d. Topical testosterone 45

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9. The implementation system for a REMS may include all but: 1

a. a description of how the drug will be distributed 2

b. coupons to allow discounts for low-income patients 3 c. certification of wholesalers and distributors 4 d. a database of all entities certified to use the drug 5

10. Which of the following best describes when the pharmacist is required to access the 6

iPLEDGE system to dispense isotretinoin: 7 a. When treatment with isotretinoin is initiated 8

b. Each time isotretinoin is dispensed 9 c. Whenever a female patient using isotretinoin may be pregnant or fills a prescription 10 for birth control medication 11 d. Annually along with the wholesaler 12

13

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Lesson number 036-368-15-002-H03 Answer Sheet: Expires September 21, 2017 1 Approved for one contact hour of Ohio Jurisprudence by the Ohio State Board of Pharmacy 2 3

REMS in the Community Pharmacy 4

Answer Sheet – circle the one correct best answer. Credit will be granted with seven correct. 5 Question Answer Question Answer

1 A B C D 6 A B C D

2 True False 7 A B C D

3 A B C D 8 A B C D

4 A B C D 9 A B C D

5 A B C D 10 A B C D 6 Please return by mail with check for $20 payable to James Lindon at: 7 James Lindon, Ph.D. 8 35104 Saddle Creek, Cleveland (Avon), Ohio 44011-4907 9 Phone 440-333-0011 10 You may also send payment via PayPal to JLindon at LindonLaw dot com 11

New: Submit answers at: http://www.lindonlaw.com/pharmacy-cpe/ 12 13 Please fax or e-mail, [specify one, please] my continuing education certificate to: 14

Pharmacist Name ____________________________ 15

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Ohio Pharmacist License Number _____________________ 19

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21 Copyright 2015 James Lindon, Lindon & Lindon LLC 22

Any views expressed are not necessarily those of the author or the law firm of Lindon & Lindon. 23 Program Evaluation (please circle one response to each question): 24

After completing this lesson I can achieve the lesson objectives: Yes No 25 This program was an effective way for me to learn: Yes No 26 I liked the program’s format: Yes No 27

This program fostered my mental participation: Yes No 28 This was a “user-friendly” way for me to learn: Yes No 29

I could sense some commercialism in this program: Yes No 30 If yes, please describe: ______________________________________________ 31 The faculty quality was: Great OK Needs to Improve 32

The learning material quality was: Great OK Needs to Improve 33 How long did it take to complete this program? _______________________ 34

What other topics would you like to see? ____________________________ 35 Comments welcome: ____________________________________________ 36