ANDA 202720 ANDA APPROVAL Teva Pharmaceuticals USA Attention

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Silver Spring, MD 20993

ANDA 202720

ANDA APPROVAL

Teva Pharmaceuticals USA Attention: Scott D. Tomsky Vice President, Regulatory Affairs 425 Privet Road Horsham, PA 19044

Dear Mr. Tomsky:

This is in reference to your abbreviated new drug application (ANDA) dated December 15, 2010, submitted pursuant to section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act), for Mycophenolic Acid Delayed-release Tablets, 180 mg and 360 mg.

Reference is also made to the Complete Response letter issued by this office on August 20, 2013, and to your amendments dated November 15 and 26, 2013; and February 12, March 31, June 20, and September 12, 2014. Your June 20, 2014 submission also addresses the risk evaluation and mitigation strategy (REMS) for this ANDA. We also acknowledge receipt of your communications addressing patent issues associated with this ANDA.

We have completed the review of this ANDA and have concluded that adequate information has been presented to demonstrate that the drug is safe and effective for use as recommended in the submitted labeling. Accordingly the ANDA is approved, effective on the date of this letter. The Division of Bioequivalence has determined your Mycophenolic Acid Delayed-release Tablets, 180 mg and 360 mg, to be bioequivalent and, therefore, therapeutically equivalent to the reference listed drug product (RLD), Myfortic Delayed-release Tablets 180 mg and 360 mg, respectively, of Novartis Pharmaceuticals Corp. (Novartis).

Your dissolution testing should be incorporated into the stability and quality control program using the same method proposed in your application. The “interim” dissolution specifications are as follows:

Dissolution Testing should be conducted in

Medium: Acid Stage: 0.1N HCl for 2 hours; Buffer Stage: 750 mL 0.1N Hydrochloric Acid + 250 mL Phosphate buffer, pH 6.8 Temp: 37.0 ± 0.5 °C Apparatus: II (Paddle) Speed: 50 rpm Volume: 750 mL (Acid stage); 1000 mL (Buffer stage)

Interim Specifications:

Acid Stage: NMT 5% of the labeled amount of drug in the dosage form is dissolved in 120 minutes Buffer Stage: NLT 80% (Q) of the labeled amount of drug in the dosage form is dissolved in 60 minutes.

The “interim” dissolution test(s) and tolerances should be finalized by submitting dissolution data for the first three production size batches. Data should be submitted as a Special Supplement – Changes Being Effected when there are no revisions to the “interim” specifications or when the final specifications are tighter than the “interim” specifications. In all other instances, the information should be submitted in the form of a Prior Approval Supplement.

The RLD upon which you have based your ANDA, Novartis’ Myfortic Delayed-release Tablets, is subject to periods of patent protection. The following patents are currently listed in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations (the “Orange Book”):

U.S. Patent Number Expiration Date

6,025,391 (the '391 patent) April 10, 2017 6,172,107 (the '107 patent) April 10, 2017 6,306,900 (the '900 patent) February 27, 2018

With respect to each of these patents, your ANDA contains a paragraph IV certification under section 505(j)(2)(A)(vii)(IV) of the Act stating that the patent is invalid, unenforceable, or will not be infringed by your manufacture, use, or sale of Mycophenolic Acid Delayed-release Tablets, 180 mg and 360 mg, under this ANDA. You have notified the Agency that Teva Pharmaceuticals USA (Teva) complied with the requirements of section 505(j)(2)(B) of the Act, and that litigation was initiated against Teva for infringement of all three patents within the statutory 45-day period in the United States District Court for the District of Delaware [Novartis AG and Novartis Pharmaceuticals Corporation v. Teva Pharmaceuticals USA, Civil Action No. 1:11-cv-00353]. Subsequently, you notified the Agency that the case was dismissed.

RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS (REMS)

Section 505-1 of the Act authorizes FDA to require the submission of a REMS if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks [section 505-1(a)]. The details of the REMS requirements were outlined in the REMS notification letter dated September 21, 2011.

The REMS consists of a Medication Guide and elements to assure safe use (ETASU). We remind you that section 505-1(f)(8) of the Act prohibits holders of an approved covered application with elements to assure safe use from using any element to block or delay approval of an application under section 505(b)(2) or (j). A violation of this provision in section 505-1(f) could result in enforcement action.

Your proposed REMS, submitted on June 20, 2014, and appended to this letter, is approved.

This REMS will use a single, shared system for the ETASU and the REMS assessments. This single, shared system, known as the Mycophenolate REMS, currently includes the products listed on the FDA REMS website, available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvider s/ucm111350.htm#Shared. Other products may be added in the future if additional NDAs or ANDAs are approved.

Under section 505-1(g)(2)(C), FDA can require the submission of a REMS assessment if FDA determines that an assessment is needed to evaluate whether the approved strategy should be modified to ensure the benefits outweigh the risks of the drug or to minimize burden on the healthcare system of complying with the REMS. Additionally, the details for what should be included in any joint assessments completed under the Mycophenolate REMS Program are listed in Appendix 1.

Prominently identify the submission containing a proposed modification of the REMS or any REMS assessments with the following wording in bold capital letters at the top of the first page of the submission:

ANDA 202720 REMS ASSESSMENT

NEW SUPPLEMENT FOR ANDA 202720 PROPOSED REMS MODIFICATION

Under section 506A of the Act, certain changes in the conditions described in this ANDA require an approved supplemental application before the change may be made.

Postmarketing reporting requirements for this ANDA are set forth in 21 CFR 314.80-81 and 314.98. The Office of Generic Drugs should be advised of any change in the marketing status of this drug.

Promotional materials may be submitted to FDA for comment prior to publication or dissemination. Please note that these submissions are voluntary. If you desire comments on proposed launch promotional materials with respect to compliance with applicable regulatory requirements, we recommend you submit, in draft or mock-up form, two copies of both the promotional materials and package insert(s) directly to:

Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705

We call your attention to 21 CFR 314.81(b)(3) which requires that all promotional materials be submitted to the Office of Prescription Drug Promotion with a completed Form FDA 2253 at the time of their initial use.

The Generic Drug User Fee Amendments of 2012 (GDUFA) (Public Law 112-144, Title III) established certain provisions with respect to self-identification of facilities and payment of annual facility fees. Your ANDA identifies at least one facility that is subject to the self identification requirement and payment of an annual facility fee. Self-identification must occur by June 1 of each year for the next fiscal year. Facility fees must be paid each year by the date specified in the Federal Register notice announcing facility fee amounts. All finished dosage forms (FDFs) or active pharmaceutical ingredients (APIs) manufactured in a facility that has not met its obligations to self-identify or to pay fees when they are due will be deemed misbranded. This means that it will be a violation of federal law to ship these products in interstate commerce or to import them into the United States. Such violations can result in prosecution of those responsible, injunctions, or seizures of misbranded products. Products misbranded because of failure to self-identify or pay facility fees are subject to being denied entry into the United States.

As soon as possible, but no later than 14 days from the date of this letter, submit, using the FDA automated drug registration and listing system (eLIST), the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is identical in content to the approved labeling (including the package insert, and any patient package insert and/or Medication Guide that may be required). Information on submitting SPL files using eLIST may be found in the guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. The SPL will be accessible via publicly available labeling repositories.

Sincerely yours,

For CAPT Jason J.Y. Woo, MD, MPH Acting Director Office of Regulatory Operations Office of Generic Drugs

Enclosures: Appendix 1 - REMS

Appendix 1

Because Mycophenolate will be a member of the Mycophenolate REMS, the assessment plan will be the same assessment plan required for the other products covered by this single, shared system. Because the 6-month, and 12-month assessments have been submitted, the assessment plan for Mycophenolate will align with the third and subsequent assessments of the Mycophenolate REMS. Therefore, your REMS assessment plan should include, but is not limited to the following:

Scheduled REMS Assessments The fourth assessment, due September 25, 2015, and annually thereafter, should include, but is not limited to the following:

1. With regard to the assessment of the Medication Guide:

i. An evaluation of patients’ understanding of the serious risks of mycophenolate. ii. A report on periodic assessments of the distribution and dispensing of the Medication Guide in accordance with 21 CFR 208.24. iii. A report on failures to adhere to distribution and dispensing requirements, and corrective actions taken to address noncompliance.

2. With regard to the assessment of the REMS material distribution, education, and support services:

i. The numbers of the Mycophenolate REMS Overview for Patients and Your Birth Control Options downloaded from the Mycophenolate REMS website or ordered from the call center.

3. With regard to Prescriber Training:

i. The number of healthcare providers who completed the Prescriber Training Confirmation form in the Mycophenolate REMS (during the reporting period and cumulative), stratified by prescriber specialty. Provide an analysis comparing the number of healthcare providers who completed the Prescriber Training Confirmation form to the estimated total number of healthcare providers prescribing a mycophenolate-containing product. Include a description of the database(s) used and methodology for identifying the number of healthcare providers. ii. A summary of the method prescribers used to complete the Prescriber Training Confirmation form (i.e., online, phone, fax). iii. The number of healthcare providers who have confirmed training and were actively prescribing mycophenolate during the reporting period (i.e., have written at least one prescription in the time period), stratified by prescriber specialty. iv. The number of healthcare providers who have prescribed mycophenolate who have not confirmed training (during the reporting period and cumulative). v. The number of newly identified prescribers and the number of new prescribers who were sent materials (monthly; during the reporting period).

4. With regard to Center Training: i. The total number of centers, stratified by type of center, that confirmed training (during the reporting period and cumulative). ii. A descriptive summary of how newly confirmed centers incorporated the mycophenolate REMS into their center’s practice (as described on the Center Training Confirmation form). iii. Total prescribers confirmed by centers.

5. With regard to Risk of Teratogenicity:

i. The number of patients receiving mycophenolate stratified by age, gender, and other demographics (during the reporting period and cumulatively over time). ii. An analysis of the post-marketing cases of pregnancy reported in association with mycophenolate (during the reporting period and cumulative) with attention to but not limited to: a. the number of pregnancy exposures* reported (during the reporting period and cumulative) and stratified by source (spontaneous report, reported via the REMS call center, enrolled in the pregnancy registry), age, and other demographics, and if the prescriber completed the REMS training. b. the pregnancy outcome for each exposed pregnancy reported (during the reporting period and cumulative). c. the root cause analysis of each pregnancy reported to determine the cause of the pregnancy exposure (during the reporting period and cumulative). iii. An evaluation of healthcare providers’ understanding of teratogenicity associated with mycophenolate.

*All pregnancy exposures reported to the sponsors from any source should be reported and analyzed as part of the REMS assessment. The cases should be linked to allow matching of the cases reported in the Pregnancy Registry to cases in the global safety database.

6. Based on the information submitted, an assessment of and conclusion regarding whether the REMS is meeting its goals, and whether modifications to the REMS are needed, including measures that would be taken to increase awareness if surveys of patients or healthcare providers indicate that awareness is not adequate.

7. An assessment of the extent to which the elements to assure safe use are meeting the goal or goals to mitigate a specific serious risk listed in the labeling of the drug, or whether the goal or goals or such elements should be modified.

Initial REMS Approval: 09/25/2012 Most Recent Modification: 09/2013

RISK EVALUATION AND MITIGATION STRATEGY (REMS)

Single Shared System for Mycophenolate

I. GOALS

The goals of the Mycophenolate REMS are:

1. To prevent unplanned pregnancy in patients using mycophenolate and to minimize fetal exposure to mycophenolate by informing prescribers and females of reproductive potential about: • the increased risk of first trimester pregnancy loss and congenital malformation associated with exposure to mycophenolate during pregnancy; and • the importance of pregnancy prevention and planning 2. To minimize the risks associated with fetal exposure to mycophenolate by collecting information on pregnancy outcomes through the Mycophenolate Pregnancy Registry 3. To inform patients about the serious risks associated with mycophenolate.

II. REMS ELEMENTS

A. Medication Guide

A Medication Guide will be dispensed with each mycophenolate prescription in accordance with 21 CFR 208.24.

The Medication Guides for mycophenolate-containing products are part of the Mycophenolate REMS and will be available on the Mycophenolate REMS website (www.MycophenolateREMS.com).

B. Elements to Assure Safe Use

1. Healthcare providers who prescribe mycophenolate will receive training. a) Mycophenolate sponsors will ensure that training will be provided to healthcare providers who prescribe mycophenolate-containing products. To become trained, each prescriber will be provided with the Mycophenolate Program Brochure for Healthcare Providers. The brochure includes the following information: i. The risk of first trimester pregnancy loss and congenital malformations associated with mycophenolate ii. Importance of educating females of reproductive potential about the increased risk of first trimester pregnancy loss and congenital malformations associated with exposure to mycophenolate during pregnancy iii. Importance of prescribers providing or facilitating patient education about pregnancy prevention and planning, including acceptable methods of contraception during mycophenolate treatment

iv. Importance of only prescribing mycophenolate to a pregnant patient if the benefits of initiating or continuing treatment outweigh the risk of fetal harm v. Importance of reporting to the Pregnancy Registry any pregnancies that occur during mycophenolate treatment or within 6 weeks following discontinuation of treatment vi. Importance of encouraging pregnant patients to participate in the Pregnancy Registry vii. Importance of obtaining a signed Patient-Prescriber Acknowledgement Form from each female of reproductive potential. The Patient-Prescriber Acknowledgement Form is part of the Mycophenolate REMS and is appended b) Mycophenolate sponsors will ensure that prescribers can successfully report that they have taken the training via the Mycophenolate REMS website, mail, fax, or by scanning and e-mailing the Prescriber Training Confirmation Form. The Prescriber Training Confirmation Form is part of the Mycophenolate REMS and is appended. c) Mycophenolate sponsors will maintain a list of all healthcare providers (HCPs) who have completed the Mycophenolate REMS Training. d) Mycophenolate sponsors will redistribute the training materials every two years or following substantive changes that affect the Mycophenolate REMS. Substantive changes are defined as 1) significant changes to the operation of the Mycophenolate REMS; 2) changes to the Prescribing Information and Medication Guide that affect the risk-benefit profile of mycophenolate. e) Mycophenolate sponsors will provide educational materials and a DHCP Letter for Centers to centers (e.g., transplant centers) that choose to administer training to their prescribers through their own centralized process. Mycophenolate sponsors will ensure that a designee of the Center can successfully report the healthcare providers who have participated in the training via the Mycophenolate REMS website, mail, fax, or by scanning and e- mailing the Center Training Confirmation Form. The Center Training Confirmation Form is part of the Mycophenolate REMS and is appended. The DHCP Letter for Centers is part of the Mycophenolate REMS and is appended. f) Mycophenolate sponsors will submit for publication a Journal Information Piece in the following journals: • Transplantation • American Journal of Transplantation • Neurology • Arthritis & Rheumatism • Journal of the American Academy of Dermatology • Journal of the American Society of Nephrology

• Obstetrics and Gynecology • Pediatrics • American Family Physician This piece is designed to convey the risks of mycophenolate products, the importance of completing the training, and details on where and how educational materials can be accessed. It will appear monthly for the first 6 months after FDA approval of the REMS and every other month in the subsequent 6 months. The Journal Information Piece is part of the Mycophenolate REMS and is appended. g) Mycophenolate sponsors will ensure that no later than 8 weeks after approval of the REMS, a Dear Healthcare Professional (DHCP) Introductory Letter will be sent to all HCPs who prescribed mycophenolate in the 24 months preceding REMS approval, accompanied by program materials (Prescriber Kit and Patient Kit). Mycophenolate sponsors will ensure that no later than 8 weeks after approval of the REMS, a DHCP Introductory Letter will be sent to all HCPs who: are on the following American Medical Association subspecialty lists: allergy and immunology, immunology, cardiology, dermatology [including surgery, and dermatopathology], gastroenterology, neurology [including surgery and neuropathology], OB/GYN [including maternal fetal medicine], general surgery, thoracic surgery, transplantation surgery, hepatology, nephrology, and rheumatology and all corresponding pediatric subspecialties, and; have not prescribed mycophenolate in the 24 months preceding REMS approval. The DHCP Introductory Letter is designed to convey and reinforce the increased risks of first trimester pregnancy loss and congenital malformation associated with mycophenolate exposure during pregnancy and the importance of prescribers completing the training and will include important safety information about products that contain mycophenolate. The DHCP Introductory Letter will also provide details on where and how educational materials can be ordered. The letter will be available on the Mycophenolate REMS website for 1 year from the date of distribution. The DHCP Introductory Letter is part of the Mycophenolate REMS and is appended. h) Mycophenolate sponsors will maintain a call center to support prescribers interfacing with the Mycophenolate REMS. i) Mycophenolate sponsors will monitor distribution and prescription data monthly to identify new prescribers who should be trained.

j) The following materials are part of the Mycophenolate REMS and are appended: • Mycophenolate REMS Brochure for Healthcare Providers • Patient-Prescriber Acknowledgement Form • Prescriber Training Confirmation Form • Center Training Confirmation Form • DHCP Letter for Centers • Journal Information Piece • DHCP Introductory Letter • Obstetrician/Gynecologist Referral Template Letters for Contraception Counseling • Obstetrician/Gynecologist Referral Template Letters for Preconception Counseling • Mycophenolate REMS Overview for Patients and Your Birth Control Options • Mycophenolate Pregnancy Registry Frequently Asked Questions for Patients • Mycophenolate REMS Website These materials will also be available on the Mycophenolate REMS website or by calling the Mycophenolate REMS call center at 1-800-617-8191.

2. Mycophenolate sponsors will maintain a centralized pregnancy registry for females who become pregnant and consent to participate. The primary objectives of the Pregnancy Registry are to: • Document maternal and fetal outcomes of each exposed pregnancy to further characterize the risk of mycophenolate fetal exposure. • Determine mycophenolate exposure status for each reported pregnancy • Understand the circumstances that led to the fetal exposure (root cause analysis) • Identify factors that affect the risk of adverse outcomes such as dose, timing of exposure, or maternal characteristics

III. Timetable for Submission of Assessments

Mycophenolate NDA sponsors will submit REMS assessments to FDA every 6 months for the first year from the date of initial approval of the Mycophenolate REMS and annually thereafter. To facilitate inclusion of as much information as possible while allowing reasonable time to prepare the submission, the reporting interval covered by

each submission will conclude no earlier than 60 days before the submission date for that assessment. The assessment will be submitted so that it is received by the FDA on or before the due date.

BROCHURE FOR HEALTHCARE PROVIDER

Table of Contents

Introducing Mycophenolate REMS………………………………………………………………………………………………………………………………3

Mycophenolate-Related First Trimester Pregnancy Loss and Congenital Malformations……………………………………………….5

Your Role in Mycophenolate REMS………………………………………………………………………………………………………………..……………6

Reporting a Pregnancy……………………………………………………………………………………………………………………………………………..10

Frequently Asked Questions About Mycophenolate REMS and the Mycophenolate Pregnancy Registry………………………11

Mycophenolate REMS Resources………………………………………………………………………………………………………………………………14

Introducing Mycophenolate REMS

Mycophenolate REMS (Risk Evaluation and Mitigation Strategy) The goals of the Mycophenolate REMS are: has been mandated by the FDA (Food and Drug Administration) 1. To prevent unplanned pregnancy in patients using due to postmarketing reports showing that exposure to mycophenolate and to minimize fetal exposure to mycophenolate during pregnancy is associated with increased risks mycophenolate by informing prescribers and females of first trimester pregnancy loss and congenital malformations. of reproductive potential about: While available data are limited, structural malformations occur in approximately 20% of live-born infants exposed in utero to  The increased risks of first trimester pregnancy † mycophenolate and first trimester pregnancy loss rates are higher.* loss and congenital malformations associated The FDA determined that a REMS is necessary to ensure that the with exposure to mycophenolate during benefits of mycophenolate outweigh the risks of first trimester pregnancy; and pregnancy loss and congenital malformations associated with  The importance of pregnancy prevention mycophenolate use during pregnancy. and planning 2. To minimize the risks associated with fetal Mycophenolate is available by prescription as: exposure to mycophenolate by collecting ®  CellCept (mycophenolate mofetil) information on pregnancy outcomes  Myfortic® (mycophenolic acid) through the Mycophenolate Pregnancy  Generic formulations of mycophenolate mofetil Registry  Generic formulations of mycophenolic acid 3. To inform patients about the serious risks associated with mycophenolate

*Sifontis NM, et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation. 2006;82:1698-1702. †Prescribing Information for mycophenolate.

For complete safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com 3

Introducing Mycophenolate REMS (cont’d)

All prescribers of mycophenolate and females of reproductive This brochure, the Mycophenolate REMS Brochure for Healthcare potential, whether or not they plan to get pregnant, should be Providers, has been designed to help you understand the components aware of the risks associated with mycophenolate. of Mycophenolate REMS. Included are details on what you can do to help ensure the successful implementation of Mycophenolate REMS Females of reproductive potential include girls who have so that patients understand the risks associated with exposure to entered puberty and all women who have a uterus and have not mycophenolate during pregnancy. passed through menopause.

Menopause is the permanent end of menstruation and fertility.

Menopause should be clinically confirmed by a patient’s healthcare practitioner. Some commonly used diagnostic criteria include: 1. 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy); or 2. Postsurgical from a bilateral oophorectomy

Mycophenolate-Related First Trimester Pregnancy Loss and Congenital Malformations

Mycophenolate can cause fetal harm when administered The reported malformations were similar to findings in to a pregnant female. Exposure to mycophenolate during animal reproductive toxicology studies. For comparison, pregnancy is associated with an increased risk of: background rate for congenital anomalies in the United  First trimester pregnancy loss States is about 3% and the NTPR data show a rate of 4%  Congenital malformations (especially external ear and to 5% among babies born to organ-transplant patients abnormalities such as a cleft lip and palate) using other immunosuppressive drugs. Because these  Anomalies in babies of the distal limbs, heart, esophagus and postmarketing data are reported voluntarily, it is not kidney always possible to reliably estimate the frequency of particular outcomes. In December 2006, the National Transplantation Pregnancy Registry (NTPR) published data from When initiating or continuing treatment with prospective cases where 24 female transplant patients mycophenolate, you should educate females of reported 33 mycophenolate-exposed pregnancies.* reproductive potential on the risks associated with Of these pregnancies, there were: exposure to mycophenolate during pregnancy. They need to make informed decisions about treatment.  15 spontaneous abortions (45%)  18 live-born infants

– Four of the 18 live-born infants had structural malformations (22%)

Of the 77 females exposed to systemic mycophenolate during pregnancy that were reported in postmarketing data† (collected between 1995 and 2007):

 25 had spontaneous abortions  14 had a malformed fetus or infant – Six of the 14 malformed offspring had ear abnormalities

Your Role in Mycophenolate REMS

You need to complete the following steps to help ensure As a prescriber of mycophenolate, you should enroll in the successful implementation of Mycophenolate REMS Mycophenolate REMS by completing a Prescriber with females of reproductive potential: Training Confirmation Form to document that you understand, and will comply with Mycophenolate REMS. 1. Enroll in Mycophenolate REMS 2. Check Pregnancy Status You can submit a Prescriber Training Confirmation Form 3. Educate Females of Reproductive Potential to Mycophenolate REMS by one of several ways: 4. Obtain a Signed Patient-Prescriber Acknowledgment  Visit www.MycophenolateREMS.com and complete the online Form form 5. Report Any Mycophenolate-Exposed Pregnancies  Complete a hard copy and submit it via fax to 1-800-617-5768  1. Enroll in Mycophenolate REMS Complete a hard copy and mail it to: Mycophenolate REMS You should become familiar with the risks of embryofetal toxicity 200 Pinecrest Plaza associated with mycophenolate and the requirements of Morgantown, WV 26505-8065 Mycophenolate REMS.  Call 1-800-617-8191

This brochure is not a comprehensive description of the risks associated with the use of mycophenolate.

Your Role in Mycophenolate REMS (cont’d)

2. Check Pregnancy Status

You must determine if females of reproductive potential are pregnant:  Provide females of reproductive potential with a Mycophenolate REMS Overview & Your Birth  One pregnancy test with a sensitivity of at least Control Options booklet. 25 mIU/mL should be done immediately before You should ensure that they understand their role starting mycophenolate in Mycophenolate REMS.  Another pregnancy test with the same sensitivity  Provide pregnancy planning education should be done 8 to 10 days later Advise patients using mycophenolate to let you know  Repeat pregnancy tests should be performed at routine follow- if they are considering pregnancy. For a patient up visits considering pregnancy, determine whether there are  Results of all pregnancy tests should be discussed with the appropriate treatment options with less potential for patient embryofetal toxicity. In addition, it is important to optimize the patient’s underlying medical condition(s) and nutritional status prior to conception. Refer In the event of a positive pregnancy test, discuss the risks patients for pre-conception counseling and high risk obstetrical and benefits of treatment with the patient. The patient should be care as needed and coordinate care among apprised of the potential hazard to the fetus. In certain the patient’s established providers. situations, you and the patient may decide the maternal  Provide contraception counseling benefits outweigh the risks to the fetus. Unless patients choose not to have sexual intercourse 3. Educate Females of Reproductive Potential with a man at any time (abstinence), you must instruct them to always use acceptable contraception:  Educate females about the risks of mycophenolate – During entire treatment with mycophenolate exposure during pregnancy. – For 6 weeks after they stop taking mycophenolate Before initiating or continuing treatment, you must

educate females of reproductive potential by discussing with them the increased risks of first trimester pregnancy loss and congenital malformations associated with exposure to mycophenolate during pregnancy. The information you share in this discussion will be reinforced by the Mycophenolate REMS Overview & Your Birth Control Options booklet.

Your Role in Mycophenolate REMS (cont’d)

The following table lists the forms of contraception that are acceptable for use during treatment with mycophenolate. Guide your patients to choose from the following birth control options:

Acceptable Contraception Methods for Females of Reproductive Potential*

Option 1  Intrauterine devices (IUDs)  Tubal sterilization Methods to Use Alone  Patient’s partner had a vasectomy

Option 2 Hormone Methods Barrier Methods

choose 1 choose 1

Choose One Hormone Method

AND One Barrier Method Estrogen and Progesterone  Diaphragm with spermicide

 Oral contraceptive pill  Cervical cap with spermicide

 Transdermal patch  Contraceptive sponge  Vaginal ring AND  Male condom   Progesterone-only Female condom

 Injection

 Implant

Option 3 Barrier Methods Barrier Methods

choose 1 choose 1 Choose One Barrier Method   from each column (must Diaphragm with spermicide Male condom choose two methods)  Cervical cap with spermicide AND  Female condom  Contraceptive sponge

*Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause.

Your Role in Mycophenolate REMS (cont’d)

EMERGENCY CONTRACEPTION 5. Report any pregnancies to the Mycophenolate Pregnancy Registry Patients should also be counseled on the availability of emergency contraception in the event they have The Mycophenolate Pregnancy Registry has been intercourse without acceptable contraception or their established to evaluate mycophenolate-exposed contraceptive methods fail. Patients 17 years and older pregnancies and their outcomes. This will provide an can purchase emergency contraception over the counter. opportunity to learn more about mycophenolate exposure Patients can call the Emergency Contraception Hotline* in utero. at 1-888-NOT-2-LATE (1-888-668-2528) to get information Instruct patients to tell you if they get pregnant during on how to obtain emergency contraception. * treatment with mycophenolate or within 6 weeks Mycophenolate REMS is neither affiliated with nor an endorser of this following discontinuation of treatment. If you learn that a organization. The information provided by Mycophenolate REMS or this patient is pregnant: organization is meant for informational purposes only, and is not intended to replace medical advice to your patients.  Report the pregnancy to the Mycophenolate Pregnancy 4. Obtain a signed Patient-Prescriber Registry

Acknowledgment Form – By phone: 1-800-617-8191 After you have educated females of reproductive potential – Online: www.MycophenolatePregnancyRegistry.com; on the risks associated with exposure to mycophenolate or during pregnancy and have counseled them on – By mail: contraception and pregnancy planning, have them Mycophenolate Pregnancy Registry acknowledge this by signing a Patient-Prescriber 201 Broadway, Suite 5 Acknowledgment Form. Cambridge, MA 02139 By signing this form, patients agree that they will comply with Mycophenolate REMS requirements. For patients who are minors, a legal guardian should sign in addition to the patient. You too, as the prescriber, should sign the form and give a copy to the patient.

Retain the original copy for your records.

Reporting a Pregnancy

Patients should be informed that you will report any pregnancies of which you become aware to the Mycophenolate Pregnancy Registry. Provision of patient contact and medical information to the Mycophenolate Pregnancy Registry is covered by an HIPAA waiver.

The Mycophenolate Pregnancy Registry program administrator will report personally identifiable pregnancy data to the appropriate drug manufacturer for purposes of reporting to regulatory agencies as required by law. Aggregated de-identified data may be shared among participating sponsors of Mycophenolate REMS and/or submitted for publication in peer-reviewed scientific journals.

 Encourage the patient to participate in the

Mycophenolate Pregnancy Registry

 Provide the patient with Mycophenolate Pregnancy Registry Frequently Asked Questions for Patients

Frequently Asked Questions About Mycophenolate REMS and the Mycophenolate Pregnancy Registry

Who is Mycophenolate REMS for? The Mycophenolate Pregnancy Registry will collect data to characterize the risks associated with exposure to Mycophenolate REMS is designed to help inform mycophenolate during pregnancy or within 6 weeks prescribers, nurses, pharmacists, and females of reproductive following discontinuation of treatment, regardless of potential of the risks associated with exposure to mycophenolate indication. There is no limit to the number or type of during pregnancy. physicians and/or patients who may contribute data to Who can participate in the Mycophenolate the Mycophenolate Pregnancy Registry. All reports of Pregnancy Registry? potential maternal and fetal exposure to mycophenolate A female patient is considered eligible if she meets either will be considered for the Mycophenolate of the following criteria: Pregnancy Registry.  A patient who is or was pregnant and was exposed to The success of the Mycophenolate Pregnancy Registry at least 1 dose of mycophenolate during pregnancy depends on the participation of both patients and  A patient who got pregnant within 6 weeks following healthcare providers. Healthcare providers should identify discontinuation of treatment patients who are currently pregnant or who may have been exposed to mycophenolate while pregnant, inform Patients who meet either of these criteria, regardless of them of the Mycophenolate Pregnancy Registry, and indication, can participate. Patients whose pregnancy encourage them to participate in the Mycophenolate does not meet these criteria may not participate in the Pregnancy Registry. Healthcare providers should report Mycophenolate Pregnancy Registry. any pregnancy that may involve exposure to Why is the Mycophenolate Pregnancy Registry mycophenolate, whether or not the patient chooses to important? participate. Patients should be informed that you will report any pregnancies of which you become aware to Exposure to mycophenolate during pregnancy is the Mycophenolate Pregnancy Registry. associated with:  Increased risks of pregnancy loss during the first trimester  Higher risk of congenital malformations – Ear abnormalities such as microtia – Facial deformities, including cleft lip and palate – Anomalies of the distal limbs, heart, esophagus, and kidney

Frequently Asked Questions About Mycophenolate REMS and the Mycophenolate Pregnancy Registry (cont’d)

What is my role in the Mycophenolate Pregnancy After I report my patient’s pregnancy, what will her Registry? participation involve? Instruct patients to tell you if they get pregnant during The patient will be asked in telephone interviews to treatment with mycophenolate or within 6 weeks answer questions regarding her health and her baby’s following discontinuation of treatment. If you learn that a patient is health. These interviews will take place during each pregnant trimester of pregnancy; near the expected time of delivery  Report the pregnancy to the Mycophenolate or at pregnancy outcome; and when the infant reaches Pregnancy Registry 2 months, 6 months, and 1 year of age. Since the  Encourage the patient to participate in the Mycophenolate Pregnancy Registry relies on being able to contact Mycophenolate Pregnancy Registry the patient, it is important for you to advise her to keep the Mycophenolate Pregnancy Registry informed When you report an eligible pregnancy to the of any changes to her contact information throughout her Mycophenolate Pregnancy Registry, you should participation. provide your contact information. Also provide the Mycophenolate Pregnancy Registry with information After I enroll my patient, what is my role? about the pregnancy and the patient’s contact information You will be asked to provide pregnancy and outcomes so that she can be called for follow-up for this safety data on a paper-based case report form (CRF) and submit study. Provision of patient contact and medical it via mail or fax, or enter the data into an electronic data information to the Mycophenolate Pregnancy capture (EDC) system. You must keep the Mycophenolate Registry is covered by an HIPAA waiver. Pregnancy Registry informed of any changes to your When patients participate in the Mycophenolate contact information throughout your participation. Pregnancy Registry, they agree to provide information about their pregnancy, including information about

prenatal drug exposure of any duration, maternal demography and history, and maternal and fetal outcomes of pregnancies exposed to mycophenolate. Patients are encouraged to participate in the Mycophenolate Pregnancy Registry as soon as their

pregnancy is known, preferably in the first trimester.

Frequently Asked Questions About Mycophenolate REMS and the Mycophenolate Pregnancy Registry (cont’d)

How will data collected by the Mycophenolate Pregnancy Registry be analyzed and reported? How can I obtain more information? The Mycophenolate Pregnancy Registry program  Visit administrator will report personally identifiable www.MycophenolatePregnancyRegistry.com pregnancy data to the appropriate drug manufacturer for purposes of reporting to regulatory agencies as required  Visit www.MycophenolateREMS.com by law. Aggregated de-identified data may be shared among participating sponsors of Mycophenolate REMS  Call 1-800-617-8191 and/or submitted for publication in peer-reviewed scientific journals.

Do I still report pregnancies to the National Transplantation Pregnancy Registry (NTPR)? All pregnancies occurring during treatment with mycophenolate or within 6 weeks following discontinuation of treatment should be reported to the Mycophenolate Pregnancy Registry, regardless of indication, for inclusion and follow-up. In addition to reporting exposed pregnancies to the Mycophenolate Pregnancy Registry, you may also report pregnancies to the NTPR.

Mycophenolate REMS Resources prescribers of mycophenolate to help establish a Several resources have been developed to help ensure working relationship with an OB/GYN for patient that you and your patients understand the risks counseling. There are 2 letter templates—one for associated with exposure to mycophenolate during contraception counseling and one for pregnancy pregnancy and to help you comply with the requirements planning education—that can be customized for your of Mycophenolate REMS. These resources, some of which practice and patient before sending to an OB/GYN have been described previously, are available either in the Mycophenolate REMS Overview & Your Birth Control Options or online. They include:  Medication Guide There is a separate Medication Guide for each  Mycophenolate REMS Web Site: mycophenolate formulation www.MycophenolateREMS.com  Mycophenolate REMS Overview & Your Birth The Web site provides information about Mycophenolate REMS, including the option to order or download resource Control Options materials. Enrollment in Mycophenolate REMS can also This booklet helps patients understand Mycophenolate be completed on this site REMS and gives patients an overview of acceptable forms of contraception. Included in the booklet are  Mycophenolate REMS Brochure for Healthcare – Patient-Prescriber Acknowledgment Form Providers (this brochure) HCPs and females of reproductive potential sign this to acknowledge that they have been  Prescriber Training Confirmation Form informed about the risks and will comply with Prescribers enroll in Mycophenolate REMS by Mycophenolate REMS completing this form – Mycophenolate Pregnancy Registry Frequently Asked Questions for Patients  Center Training Confirmation Form This document answers some common questions Centers enroll in Mycophenolate REMS by completing about the Mycophenolate Pregnancy Registry in this form patient-friendly language

 Obstetrician/Gynecologist Referral Template Letters These customizable letters available online at www.MycophenolateREMS.com can be used by

Mycophenolate REMS Resources (cont’d)

 Mycophenolate Pregnancy Registry Additional Resources The Mycophenolate Pregnancy Registry evaluates FOR MORE INFORMATION ABOUT CONTRACEPTION* mycophenolate-exposed pregnancies and their outcomes. You can contact the Mycophenolate  Association of Reproductive Health Professionals: www.arhp.org Pregnancy Registry by calling 1-800-617-8191 or visiting www.MycophenolatePregnancyRegistry.com  Planned Parenthood: www.plannedparenthood.org For more information about Mycophenolate REMS and for all resource materials FOR MORE INFORMATION ABOUT BIRTH DEFECTS*  Centers for Disease Control and Prevention: www.cdc.gov  www.MycophenolateREMS.com Visit

 1-800-617-8191 *Mycophenolate REMS is neither affiliated with nor an endorser of these Call organizations. The information provided by Mycophenolate REMS or these organizations is meant for informational purposes only, and is not intended to replace your medical advice to your patients.

OVERVIEW & YOUR BIRTH CONTROL OPTIONS BOOKLET

PROGRAM OVERVIEW FOR PATIENTS

Table of Contents

Welcome to Mycophenolate REMS ...... 3

What You Need to Know ...... 4

Your Role ...... 5

Your Birth Control Options ...... 6

Reporting Your Pregnancy ...... 8

Important Resources ...... 9

Other Resources ...... 10

PROGRAM OVERVIEW FOR PATIENTS

Welcome to Mycophenolate REMS

Females who take mycophenolate and can get pregnant should participate in Mycophenolate REMS (Risk Evaluation and Mitigation Strategy). Mycophenolate REMS has been designed to tell you about the risks of taking mycophenolate.

Females taking mycophenolate while they are pregnant have a higher risk of miscarriage in the first 3 months. There is also a higher risk that the baby will have birth defects.

These medicines contain mycophenolate:

 CellCept® (mycophenolate mofetil)

 Myfortic® (mycophenolic acid)  Generic formulations of mycophenolate mofetil  Generic formulations of mycophenolic acid

This booklet, the Mycophenolate REMS Overview & Your Birth Control Options, tells you what you need to know about Mycophenolate REMS. It explains how it works and what your role is.

Please read all of the information in this booklet. Talk with your doctor if you have questions. Program Overview & Your Birth Control Options

For complete safety information, please the Medication Guide, which can be found at www.MycophenolateREMS.com 4

What You Need to Know

If you are a girl or woman who can get pregnant, If you are thinking about having a baby your doctor will talk with you about the risks of  Tell your doctor right away mycophenolate during pregnancy. Talk with your doctor about birth control and pregnancy planning.  Do not stop taking mycophenolate on your own You must always use acceptable birth control  In some cases, you and your doctor may decide that your medicine is more important to your health than  During your entire treatment with the possible risks to your unborn baby mycophenolate If you get pregnant while you are taking mycophenolate or  For 6 weeks after you stop taking within 6 weeks after you stop, tell your doctor right away. mycophenolate Unless you choose not to have sexual intercourse with a man at any time (abstinence), you must always use acceptable birth control. It is important to talk with your doctor about the best forms of birth control for you. The table on page 7 lists your options for birth control during treatment with mycophenolate.

Your Role

If you are a girl or woman who can get pregnant, you 5. If you are thinking about having a baby, talk with should take part in Mycophenolate REMS while you are your doctor right away. taking mycophenolate. 6. If you get pregnant while you are taking Steps you need to take: mycophenolate or within 6 weeks after you stop, 1. Talk with your doctor about mycophenolate use and tell your doctor right away. risk of miscarriage or birth defects. 7. If you get pregnant while you are taking 2. Sign the Patient-Prescriber Acknowledgment Form. mycophenolate, participate in the Mycophenolate 3. Decide with your doctor what birth control methods Pregnancy Registry. The information you provide helps are right for you. patients and doctors understand the effects of mycophenolate during pregnancy. 4. You should have one pregnancy test immediately before starting mycophenolate and another pregnancy test 8 to 10 days later. Pregnancy tests should be repeated during routine follow-up visits with your doctor. Talk to your doctor about the results of all of your pregnancy tests.

Your Birth Control Options

Mycophenolate could reduce the effectiveness of Choosing birth control is very personal. This booklet gives hormonal methods of birth control. you information on birth control methods you can use while taking mycophenolate. This information should be  Hormonal methods of birth control must be used used along with your doctor’s medical advice. After you with a barrier method because studies show that read this booklet, talk with your doctor or mycophenolate decreases blood levels of certain obstetrician/gynecologist. Then you and your doctor hormones in the oral contraceptive pill. It is can decide what is best for you. possible that mycophenolate could reduce the You must always use acceptable birth control effectiveness of the oral contraceptive pill  The effectiveness of other hormone methods (like the  During your entire treatment with mycophenolate patch, the ring, the shot, and the implant) may also  For 6 weeks after you stop taking mycophenolate be reduced while you are taking mycophenolate Unless you choose not to have sexual intercourse with a The table on page 7 lists your options for birth control man at any time (abstinence), you must always use during treatment with mycophenolate. acceptable birth control.

You may need to use more than one method of birth control at the same time. If you use an intrauterine device (IUD), had sterilization surgery (had your tubes tied or blocked), or if your partner has had a vasectomy, you do not need to use a second form of birth control.

Your Birth Control Options (cont’d) The table below lists your options for birth control during treatment with mycophenolate. Pick from the following birth control options:

Acceptable Contraception Methods

Option 1  Intrauterine devices (IUDs)  Tubal sterilization Methods to Use Alone  Patient’s partner had a vasectomy

OR Option 2 Hormone Methods Barrier Methods

choose 1 choose 1 Choose One Hormone Method  AND One Barrier Method Estrogen and Progesterone Diaphragm with spermicide  Oral contraceptive pill  Cervical cap with spermicide  Transdermal patch  Contraceptive sponge  Vaginal ring AND  Male condom   Progesterone-only Female condom  Injection  Implant OR Option 3 Barrier Methods Barrier Methods

choose 1 choose 1 Choose One Barrier Method   From Each Column (must Diaphragm with spermicide Male condom choose two methods)  Cervical cap with spermicide AND  Female condom  Contraceptive sponge

Reporting Your Pregnancy

If you get pregnant while taking mycophenolate or within 6 weeks after you stop, call your doctor right away. Do not stop taking your mycophenolate. Your doctor will talk with you about taking part in the Mycophenolate Pregnancy Registry.

Your doctor should report pregnancies to the Registry. If you would like to report a pregnancy to the Registry yourself:

 Call 1-800-617-8191 and choose “Mycophenolate Pregnancy Registry” from the menu, or  Visit www.MycophenolatePregnancyRegistry.com

Important Resources

There are many resources to help you get the  Mycophenolate REMS Web site: information you need about Mycophenolate REMS. www.MycophenolateREMS.com  Mycophenolate REMS Overview & Your Birth Provides access to all Mycophenolate REMS resources Control Options (this booklet) and materials.  Patient-Prescriber Acknowledgment Form  Mycophenolate Pregnancy Registry After a discussion with your doctor about Collects information about pregnancies that occur during mycophenolate use and risk of miscarriage or birth treatment with mycophenolate or within 6 weeks after defects, both of you will sign this form. It is included stopping. You can contact the Registry with this booklet by calling 1-800-617-8191 or by visiting www.MycophenolatePregnancyRegistry.com  Medication Guide for mycophenolate Gives you important safety information you need  Mycophenolate Pregnancy Registry Frequently Asked to know about your medicine Questions for Patients Provides answers to frequently asked questions about the  Your doctor Registry. You can obtain this from your healthcare provider or by visiting: www.MycophenolateREMS.com

Other Resources

For more information about birth control* For more information about Mycophenolate REMS  Association of Reproductive Health Professionals:  Read the Mycophenolate REMS Overview & Your Birth www.arhp.org Control Options (this booklet)  Planned Parenthood: www.plannedparenthood.org  Talk with your doctor  Visit the Mycophenolate REMS Web site: For emergency birth control* www.MycophenolateREMS.com  Call your doctor or pharmacy  Call 1-800-617-8191  Emergency Contraception Hotline: 1-888-NOT-2-LATE (1-888-668-2528)

*Mycophenolate REMS is neither affiliated with nor an endorser of these organizations. The information provided by Mycophenolate REMS or these organizations is meant for informational purposes only, and is not intended to replace your doctor’s medical advice.

FREQUENTLY ASKED QUESTIONS FOR PATIENTS

MYCOPHENOLATE PREGNANCY REGISTRY FREQUENTLY ASKED QUESTIONS FOR PATIENTS

What is the Mycophenolate Pregnancy Registry? The Registry collects information about pregnancies that occur during treatment with mycophenolate or within 6 weeks after stopping.

Why should I take part in the Mycophenolate Pregnancy Registry? The information you provide to the Registry will help us better understand the effects of mycophenolate in pregnancy. When you take part in the Registry, you provide important information that may help you and other women who take mycophenolate during their pregnancies. Women taking mycophenolate while they are pregnant have a higher risk of miscarriage in the first 3 months. There is also a higher risk that the baby will have birth defects.

Who can be in the Mycophenolate Pregnancy Registry? 1. All females who get pregnant while taking mycophenolate and 2. All females who get pregnant within 6 weeks after stopping treatment with mycophenolate

These medicines contain mycophenolate:  CellCept® (mycophenolate mofetil)  Myfortic® (mycophenolic acid)  Generic formulations of mycophenolate mofetil  Generic formulations of mycophenolic acid

Tell your doctor right away if you get pregnant. Your doctor will report your pregnancy to the Registry. We encourage you to take part in the Registry. The information you provide to the Registry will help us better understand the effects of mycophenolate in pregnancy. All the information you provide will be kept private.

What will I need to do to take part in the Mycophenolate Pregnancy Registry? There are a few simple steps to take.

1. Tell your doctor if you get pregnant The Registry will contact you after speaking with your doctor. (Turn page)

For complete safety information, please see the Medication Guide which can be found at www.MycophenolateREMS.com

2. Complete an Informed Consent form  The Informed Consent form will be mailed to you  The form tells you what to expect with the Registry. It tells you what your rights are  By signing, you allow the Registry to ask you questions about your health and your baby’s health. The Registry will also ask for information from your doctors

3. Answer the Registry’s questions about your health and your baby’s health  After the first 3 months of pregnancy  2 more times during the next 6 months of pregnancy  At the time of expected delivery  When your baby is 2 months, 6 months and 1 year

4. Let the Registry know if your contact information changes  The Registry relies on your information to contact you. If your contact information changes, please call 1-800-617-8191

What are my rights if I take part in the Mycophenolate Pregnancy Registry?

1. You can quit at any time 2. Your privacy is protected

What if I do not want to take part in the Mycophenolate Pregnancy Registry? You only take part in the Registry if you want to do it. If you decide not to participate, it will not change your medical care.

How can I get more information?  Call 1-800-617-8191 and choose “Mycophenolate Pregnancy Registry” from the menu  Visit www.MycophenolatePregnancyRegistry.com  For more information about Mycophenolate REMS, visit www.MycophenolateREMS.com

PATIENT-PRESCRIBER ACKNOWLEDGMENT FORM

For the patient: Please read each item below. Discuss them with your doctor. Do not sign this form until you are sure you understand it.

By signing on the next page, I am stating that

1. My doctor gave me the Mycophenolate REMS Overview & Your Birth Control Options booklet.

2. I know the risks to an unborn baby if I take mycophenolate while I am pregnant. I talked with my doctor about these risks. I understand that if I get pregnant while taking mycophenolate or within 6 weeks after I stop, there is  A higher risk of losing the pregnancy (miscarriage) in the first 3 months  A higher risk that the baby will have birth defects. 3. I know I will have pregnancy tests before I start and during my mycophenolate treatment. 4. My doctor talked with me about acceptable forms of birth control. 5. Unless I choose not to have sexual intercourse with a man at any time (abstinence), I will always use acceptable birth control  During my entire treatment with mycophenolate  For 6 weeks after I stop taking mycophenolate

Information about your birth control options is provided in the Mycophenolate REMS Overview & Your Birth Control Options booklet. 6. If I am thinking about having a baby during my treatment, I will talk with my doctor right away. 7. I will tell my doctor right away if I get pregnant during my treatment or within 6 weeks after I stop. 8. I know that my doctor will report any pregnancies to the Mycophenolate Pregnancy Registry.

(Please fill out form on next page)

For complete safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com

PATIENT-PRESCRIBER ACKNOWLEDGMENT FORM

Patient Name (please print): Patient Signature: Date: Parent/Guardian Name (if patient under age 18; please print): Parent/Guardian Signature: Date:

For the prescriber (or healthcare provider acting on behalf of the prescriber):

I have fully explained to my patient (and her parent or guardian if the patient is under age 18) the nature and purpose of treatment with mycophenolate and the risks to females of reproductive potential as described on the previous page. I have asked the patient (and her parent or guardian) if she has any questions regarding her treatment and have answered those questions to the best of my ability.

Prescriber’s/Other Healthcare Provider’s Name (please print): Degree: (Circle one) MD DO NP PA Prescriber’s/Other Healthcare Provider’s Signature: Date:

PLEASE RETAIN THE ORIGINAL SIGNED DOCUMENT AND PROVIDE A COPY TO THE PATIENT.

For more information about Mycophenolate REMS and to request resource materials, please visit www.MycophenolateREMS.com or call 1-800-617-8191.

PRESCRIBER TRAINING CONFIRMATION FORM

The FDA determined that a REMS (Risk Evaluation and Mitigation Strategy) is necessary to ensure that the benefits of mycophenolate outweigh the risks of first trimester pregnancy loss and congenital malformations associated with mycophenolate use during pregnancy.

Mycophenolate is available by prescription as  CellCept® (mycophenolate mofetil)  Myfortic® (mycophenolic acid)  Generic formulations of mycophenolate mofetil  Generic formulations of mycophenolic acid As a prescriber of mycophenolate to females of reproductive potential*, I understand that I need to complete and return the Training Confirmation Form to enroll in Mycophenolate REMS.

*A female of reproductive potential includes girls who have entered puberty and all females who have a uterus and have not passed through menopause.

I agree to do the following: 1. Read and understand the full Prescribing Information for mycophenolate and the Mycophenolate REMS Brochure for Healthcare Providers. 2. Understand the risks of first trimester pregnancy loss and congenital malformations associated with mycophenolate. 3. Educate females of reproductive potential on the risks associated with exposure to mycophenolate during pregnancy. 4. Provide a Mycophenolate REMS Overview & Your Birth Control Options booklet to females of reproductive potential. 5. Provide contraception counseling to patients directly or by partnering with an OB/GYN. 6. Only prescribe mycophenolate to a pregnant patient if the benefits of initiating or continuing treatment outweigh the risk of fetal harm. 7. Discuss alternative treatments to mycophenolate with females of reproductive potential who are pregnant or considering pregnancy. 8. Follow the pregnancy testing recommendations as outlined in the full Prescribing Information for mycophenolate and the Mycophenolate REMS Brochure for Healthcare Providers. 9. Report to the Mycophenolate Pregnancy Registry any pregnancies that occur during mycophenolate treatment or within 6 weeks following discontinuation of treatment. Encourage pregnant patients to participate in the Mycophenolate Pregnancy Registry. 10. Obtain a signed Patient-Prescriber Acknowledgment Form from each female of reproductive potential. I understand that I may be contacted in the future for items pertaining to the administration of Mycophenolate REMS. (PLEASE PRINT) Complete all fields below: Prescriber Prescriber First Name: ______Last Name: ______Prescriber Degree: MD, DO, NP, PA (Circle One) Specialty Code (Select one from the back of this form) ______National Provider Identifier:______Prescsriber E-mail Address: ______Facility: ______Address 1: ______Address 2: ______City: ______State: ______ZIP: ______Telephone: ______Fax: ______Prescriber Signature: ______Date: ______Healthcare Provider acting on behalf of the prescriber: ______Degree: RN, LPN, NP, PA, RPH, PharmD, CSW (Circle One)

For complete safety Information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com

PRESCRIBER TRAINING CONFIRMATION FORM

You can submit a Prescriber Training Confirmation Form by visiting www.MycophenolateREMS.com and completing the online form.

If you prefer, you can complete the paper form and return it via fax to 1-800-617-5768 or mail it to:

Mycophenolate REMS 200 Pinecrest Plaza Morgantown, WV 26505-8065

You can also call 1-800-617-8191 to complete a Prescriber Training Confirmation Form.

For more information about Mycophenolate REMS, visit www. MycophenolateREMS.com or call 1-800-617-8191.

Specialty Specialty Code Allergy and Immunology ...... 1 Cardiology ...... 2 Dermatology ...... 3 Family Practitioner ...... 4 Gastroenterology ...... 5 Hepatology ...... 6 Internal Medicine ...... 7 Nephrology ...... 8 Neurology ...... 9 OB/GYN ...... 10 Pediatric ...... 11 Rheumatology ...... 12 Surgery ...... 13 Transplant ...... 14 Other ...... 15

CENTER TRAINING CONFIRMATION FORM

Mycophenolate is available by prescription as:  CellCept® (mycophenolate mofetil)  Myfortic® (mycophenolic acid)  Generic formulations of mycophenolate mofetil  Generic formulations of mycophenolic acid On behalf of prescribers of mycophenolate to females of reproductive potential,* (place center name here) will complete and return this training form to enroll in Mycophenolate REMS.

*A female of reproductive potential includes girls who have entered puberty and all women who have a uterus and have not passed through menopause.

We agree to do the following: 1. Read and understand the full Prescribing Information for mycophenolate and the Mycophenolate REMS Brochure for Healthcare Providers 2. Understand the risks of first trimester pregnancy loss and congenital malformations associated with mycophenolate. 3. Educate females of reproductive potential on the risks associated with exposure to mycophenolate during pregnancy. 4. Provide a Mycophenolate REMS Overview & Your Birth Control Options booklet to females of reproductive potential. 5. Provide contraception counseling to patients directly or by partnering with an OB/GYN. 6. Only prescribe mycophenolate to a pregnant patient if the benefits of initiating or continuing treatment outweigh the risk of fetal harm. 7. Discuss alternative treatments to mycophenolate with females of reproductive potential who are pregnant or considering pregnancy. 8. Follow the pregnancy testing recommendations as outlined in the full Prescribing Information for mycophenolate and the Mycophenolate REMS Brochure for Healthcare Providers. 9. Report to the Mycophenolate Pregnancy Registry any pregnancies that occur during mycophenolate treatment or within 6 weeks following discontinuation of treatment. Encourage pregnant patients to participate in the Mycophenolate Pregnancy Registry. 10. Obtain a signed Patient-Prescriber Acknowledgment Form from each female of reproductive potential. 11. Describe how your center plans to implement the program requirements (please explain/outline process below):

I understand that I may be contacted in the future for items pertaining to the administration of Mycophenolate REMS. (Please fill out form on next page) For complete safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com

CENTER TRAINING CONFIRMATION FORM

CENTER INFORMATION

(PLEASE PRINT) Center: ______Center Type (disease or specialty)* ______Address: ______City: ______State: ______ZIP: ______Phone: ______Fax: ______

Contact Person: ______Email: ______

TRAINED PRESCRIBERS

Please complete fields below:

National Degree Prescriber Name Signature of Specialty Provider Date (MD, DO, Email (Printed) Prescriber Code(s)* Identifier NP, PA) (NPI)

*A list of specialty codes can be found on page 4.

 Healthcare providers acting on behalf of the prescriber should fill out the form on the next page (Please fill out form (Please fill out form on next page)

CENTER TRAINING CONFIRMATION FORM

HEALTHCARE PROVIDERS ACTING ON BEHALF OF THE PRESCRIBER

Please complete fields below:

Degree (RN, LPN, Name of Provider Name Signature of NP, PA, Specialty Date Email Prescriber you (Printed) Provider RPH, Code(s)* are signing for PharmD, CSW)

*A list of specialty codes can be found on page 4.

(Turn page)

CENTER TRAINING CONFIRMATION FORM

You can submit a completed Center Training Confirmation Form via fax to 1-800-617-5768 or mail it to:

Mycophenolate REMS 200 Pinecrest Plaza Morgantown, WV 26505-8065

For more information about Mycophenolate REMS, visit www.MycophenolateREMS.com or call 1-800-617-8191.

Specialty Specialty Code

Allergy and Immunology ...... 1 Cardiology ...... 2 Dermatology ...... 3 Family Practitioner ...... 4 Gastroenterology ...... 5 Hepatology ...... 6 Internal Medicine ...... 7 Nephrology ...... 8 Neurology ...... 9 OB/GYN ...... 10 Pediatric ...... 11 Rheumatology ...... 12 Surgery ...... 13 Transplant ...... 14 Other ...... 15

Center Type Center Type Code Allergy and Immunology ...... 1 Cardiology ...... 2 Dermatology ...... 3 Dermatology Surgery ...... 4 Dermatopathology ...... 5 Gastroenterology ...... 6 General Surgery ...... 7 Hepatology ...... 8 Immunology ...... 9 Maternal Fetal Medicine ...... 10 Nephrology ...... 11 Neurologic Surgery ...... 12 Neurology ...... 13 Neuropathology ...... 14 OB/GYN ...... 15 Rheumatology ...... 16 Thoracic Surgery ...... 17 Transplantation Surgery ...... 18

DEAR HEALTHCARE PROVIDER LETTER

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Dear Healthcare Provider:

The goals of the Mycophenolate REMS are: 1. To prevent unplanned pregnancy in patients using mycophenolate and to minimize fetal exposure to mycophenolate by informing prescribers and females of reproductive potential about • the increased risks of first trimester pregnancy loss and congenital malformations associated with exposure to mycophenolate during pregnancy; and • the importance of pregnancy prevention and planning 2. To minimize the risks associated with fetal exposure to mycophenolate by collecting information on pregnancy outcomes through the Mycophenolate Pregnancy Registry 3. To inform patients about the serious risks associated with mycophenolate

What you need to know to prescribe mycophenolate All prescribers of mycophenolate and females of reproductive potential,* whether or not they plan to get pregnant, should participate in Mycophenolate REMS. If you prescribe mycophenolate to females of reproductive potential (new and continuing patients), you should receive training and agree to do the following:  Understand the risks of first trimester pregnancy loss and congenital malformations associated with mycophenolate  Educate females of reproductive potential on the risks associated with exposure to mycophenolate during pregnancy  Provide a Mycophenolate REMS Overview & Your Birth Control Options booklet to females of reproductive potential  Provide contraception counseling to patients directly or by partnering with an OB/GYN  Only prescribe mycophenolate to a pregnant patient if the benefits of initiating or continuing treatment outweigh the risk of fetal harm  Discuss alternative treatments to mycophenolate with females of reproductive potential who are pregnant or considering pregnancy  Follow the pregnancy testing recommendations *A female of reproductive potential includes girls who have entered puberty and all women who have a uterus and have not yet passed through menopause. (Continued on next page)

For complete safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

 Report to the Mycophenolate Pregnancy Registry any pregnancies that occur during mycophenolate treatment or within 6 weeks following discontinuation of treatment. Encourage pregnant patients to participate in the Mycophenolate Pregnancy Registry  Obtain a signed Patient-Prescriber Acknowledgement Form from females of reproductive potential

Please note that the manufacturers may contact you in the future for assessment of Mycophenolate REMS.

This letter is not a comprehensive description of the risks associated with the use of mycophenolate. For complete safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com.

For more information about Mycophenolate REMS, including all program materials and instructions on how to enroll, please visit www.MycophenolateREMS.com or call 1-800-617-8191.

The FDA requests healthcare providers report any pregnancies of which they become aware. Pregnancies that occur during treatment with mycophenolate or within 6 weeks following discontinuation of treatment should be reported by contacting the Mycophenolate Pregnancy Registry.  By phone: 1-800-617-8191  Online: www.MycophenolatePregnancyRegistry.com  Or by mail: Mycophenolate Pregnancy Registry 201 Broadway, Suite 5 Cambridge, MA 02139 Thank you for your commitment to helping patients understand the risks and benefits associated with mycophenolate treatment.

Sincerely,

Mycophenolate REMS Team

(Continued on next page)

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Indications and Important Selected Safety Information About Mycophenolate-Containing Products

INDICATIONS:

® CellCept (mycophenolate mofetil) is indicated for the WARNING: EMBRYOFETAL TOXICITY, prophylaxis of organ rejection in patients receiving MALIGNANCIES AND SERIOUS allogeneic renal, cardiac or hepatic transplants. CellCept INFECTIONS should be used concomitantly with cyclosporine and corticosteroids. Use during pregnancy is associated with

® increased risks of first trimester pregnancy Myfortic (mycophenolic acid) is indicated for the loss and congenital malformations. prophylaxis of organ rejection in patients receiving Females of reproductive potential (FRP) allogeneic renal transplants, administered in combination must be counseled regarding pregnancy with cyclosporine and corticosteroids. prevention and planning.

Mycophenolate mofetil is indicated for the prophylaxis of Immunosuppression may lead to increased organ rejection in patients receiving allogeneic renal, susceptibility to infection and possible cardiac or hepatic transplants. Mycophenolate mofetil development of lymphoma and other should be used concomitantly with cyclosporine and neoplasms. Only physicians experienced in corticosteroids. immunosuppressive therapy and management of organ transplant recipients Mycophenolic acid is indicated for the prophylaxis of should prescribe mycophenolate- organ rejection in patients receiving allogeneic renal containing products. Patients receiving transplants, administered in combination with cyclosporine mycophenolate-containing products should and corticosteroids. be managed in facilities equipped and staffed with adequate laboratory and

supportive medical resources. The CONTRAINDICATIONS: physician responsible for maintenance

therapy should have complete information . Allergic reactions to mycophenolate-containing requisite for the follow-up of the patient. products have been observed; therefore,

mycophenolate-containing products are contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product.

. CellCept Intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN

(Continued on next page)

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Important Selected Safety Information About Mycophenolate-Containing Products (cont’d)

WARNINGS: Serious Infections Embryofetal Toxicity . Patients receiving immunosuppressants, including . Mycophenolate-containing products can cause fetal mycophenolate, are at increased risk of developing harm when administered to a pregnant female. Use bacterial, fungal, protozoal and new or reactivated of mycophenolate-containing products during viral infections, including opportunistic infections. pregnancy is associated with an increased risk of These infections may lead to serious, including fatal first trimester pregnancy loss and an increased risk outcomes. of congenital malformations, especially external ear . Polyomavirus associated nephropathy (PVAN), JC and other facial abnormalities including cleft lip and virus associated progressive multifocal palate, and anomalies of the distal limbs, heart, leukoencephalopathy (PML), cytomegalovirus esophagus, and kidney. (CMV) infections, reactivation of hepatitis B (HBV) Pregnancy Exposure Prevention and Planning or hepatitis C (HCV) have been reported.

. Females of reproductive potential must be made Neutropenia aware of the increased risk of first trimester pregnancy loss and congenital malformations and . Severe neutropenia [absolute neutrophil count must be counseled regarding pregnancy prevention (ANC) <0.5 x 103/µL] developed in up to 2.0% of and planning. renal, up to 2.8% of cardiac, and up to 3.6% of Lymphoma and Malignancy hepatic transplant patients receiving mycophenolate mofetil 3g daily. . Patients receiving immunosuppressive regimens involving combinations of drugs, including . Patients receiving mycophenolate-containing mycophenolate-containing products, as part of an products should be monitored for neutropenia. immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, . If neutropenia develops [absolute neutrophil particularly of the skin. count (ANC) <1.3 x 103/µL] or anemia occurs, Combination with Other Immunosuppressive dosing with mycophenolate-containing products Agents should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the . Mycophenolate mofetil has been administered in patient managed appropriately. combination with the following agents in clinical Pure Red Cell Aplasia trials: antithymocyte globulin, OKT3, cyclosporine, and corticosteroids. . Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate- . Mycophenolic acid has been administered in containing products in combination with other combination with the following agents in clinical immunosuppressive agents. Patients receiving trials: antithymocyte/lymphocyte immunoglobulin, mycophenolate-containing products should be muromonab-CD3, basiliximab, daclizumab, monitored for blood dyscrasias. cyclosporine, and corticosteroids.

CAUTION: CELLCEPT INTRAVENOUS SOLUTION . The efficacy and safety of the use of SHOULD NEVER BE ADMINISTERED BY RAPID mycophenolate-containing products, in combination OR BOLUS INTRAVENOUS INJECTION with other immunosuppressive agents have not been determined.

(Continued on next page)

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Important Selected Safety Information About Mycophenolate-Containing Products (cont’d)

PRECAUTIONS:

Pregnancy Exposure Prevention and Planning Pregnancy Category D . Females of reproductive potential* must be . Mycophenolate-containing products can cause made aware of the increased risk of first fetal harm when administered to a pregnant trimester pregnancy loss and congenital female. If mycophenolate-containing products are malformations and must be counseled regarding used during pregnancy, or if the patient becomes pregnancy prevention and planning. pregnant while taking mycophenolate-containing products, the patient should be apprised of the . Females of reproductive potential taking potential hazard to the fetus. In certain situations, the patient and her healthcare practitioner may mycophenolate-containing products must decide that the maternal benefits outweigh the receive contraceptive counseling and use risks to the fetus. Risks and benefits of acceptable contraception during entire therapy mycophenolate-containing products should be with mycophenolate-containing products and for discussed with the patient. 6 weeks after stopping therapy (see Full Prescribing Information for acceptable . For those females using mycophenolate- contraception methods). containing products at any time during pregnancy and those becoming pregnant within . Patients should be aware that mycophenolate- 6 weeks of discontinuing therapy, the healthcare containing products reduce blood levels of the practitioner should report the pregnancy to the hormones in the oral contraceptive pill and could Mycophenolate Pregnancy Registry (1-800- theoretically reduce its effectiveness. 617-8191). The healthcare practitioner should also strongly encourage the patient to enroll in . To prevent unplanned exposure during the pregnancy registry. pregnancy, females of reproductive potential should have a serum or urine pregnancy test Gastrointestinal Disorders with a sensitivity of at least 25 mIU/mL . Gastrointestinal bleeding (requiring immediately before starting a mycophenolate- hospitalization) has been reported in de novo containing product. renal transplant patients (1.0%) and maintenance patients (1.3%) treated with . Another pregnancy test with the same sensitivity mycophenolic acid (up to 12 months); and in should be done 8 to 10 days later. Repeat approximately 3% of renal, in 1.7% of cardiac pregnancy tests should be performed during and in 5.4% of hepatic transplant patients routine follow-up visits. treated with mycophenolate mofetil 3g daily.

. Results of all pregnancy tests should be . Mycophenolate-containing products should be discussed with the patient. administered with caution in patients with active serious digestive system disease because . In the event of a positive pregnancy test, mycophenolate-containing products have been females should be counseled with regard to associated with an increased incidence of whether the maternal benefits of mycophenolate digestive system adverse events. treatment may outweigh the risks to the fetus in certain situations.

. For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity.

(Continued on next page)

Important Selected Safety Information About Mycophenolate-Containing Products (cont’d)

Concomitant Medications

. It is recommended that mycophenolate- containing products not be administered ADVERSE REACTIONS: concomitantly with azathioprine because of the potential to cause bone marrow suppression and . The principal adverse reactions associated inhibit purine metabolism. with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, . Caution should be used in the concomitant vomiting, and there is evidence of a higher administration of mycophenolate-containing frequency of certain types of infections, eg, products with drugs that interfere with opportunistic infections. Phlebitis and thrombosis enterohepatic recirculation such as have been reported with intravenous cholestyramine because of the potential to administration. reduce the efficacy of mycophenolate-containing products. . The principal adverse reactions associated with the administration of mycophenolic acid Immunizations include constipation, nausea, and urinary tract . During treatment with mycophenolate-containing infection in de novo patients and nausea, diarrhea, products, avoid the use of live attenuated and nasopharyngitis in maintenance patients. vaccines and advise patients that vaccinations may be less effective. For additional safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can Phenylketonurics be found at www.MycophenolateREMS.com

. Care should be taken if mycophenolate mofetil

oral suspension is administered to patients with

phenylketonuria. Complete blood counts should

be performed weekly during the first month, twice

monthly for the second and third months of

treatment, then monthly through the first year.

Nursing Mothers

. It is not known whether mycophenolate-

containing products are excreted in human milk.

Because many drugs are excreted in human milk,

and because of the potential for serious adverse

reactions in nursing infants from mycophenolate-

containing products, a decision should be made

whether to discontinue nursing or to discontinue

the drug, taking into account the importance of

the drug to the mother.

. Patients should not breastfeed during

mycophenolate-containing products therapy.

* A female of reproductive potential incudes girls who have entered puberty and all women who have a uterus and have not yet passed through menopause.

DEAR CENTER DIRECTOR LETTER

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Dear Center Director:

The goals of the Mycophenolate REMS are: 1. To prevent unplanned pregnancy in patients using mycophenolate and to minimize fetal exposure to mycophenolate by informing prescribers and females of reproductive potential about: • the increased risks of first trimester pregnancy loss and congenital malformations associated with exposure to mycophenolate during pregnancy; and • the importance of pregnancy prevention and planning 2. To minimize the risks associated with fetal exposure to mycophenolate by collecting information on pregnancy outcomes through the Mycophenolate Pregnancy Registry 3. To inform patients about the serious risks associated with mycophenolate

Why are you receiving this letter? To facilitate training about this risk, you can set up training at your center and enroll all healthcare providers who participate. After completing the training, all healthcare providers should read and sign the Center Training Confirmation Form sent with this letter.

What you need to know to prescribe mycophenolate All prescribers of mycophenolate and females of reproductive potential,* whether or not they plan to get pregnant, should participate in Mycophenolate REMS. Healthcare providers who prescribe mycophenolate to females of reproductive potential (new and continuing patients) should receive training and agree to do the following:  Understand the risks of first trimester pregnancy loss and congenital malformations associated with mycophenolate  Educate females of reproductive potential on the risks associated with exposure to mycophenolate during pregnancy  Provide a Mycophenolate REMS Overview & Your Birth Control Options booklet to females of reproductive potential  Provide contraception counseling to patients directly or by partnering with an OB/GYN  Only prescribe mycophenolate to a pregnant patient if the benefits of initiating or continuing treatment  outweigh the risk of fetal harm  Discuss alternative treatments to mycophenolate with females of reproductive potential who are pregnant or considering pregnancy  Follow the pregnancy testing recommendations * A female of reproductive potential includes girls who have entered puberty and all women who have a uterus and have not passed through menopause. (Continued on next page) For complete safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com (Continued on next page)

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

 Report to the Mycophenolate Pregnancy Registry any pregnancies that occur during mycophenolate treatment with or within 6 weeks following discontinuation of treatment. Encourage pregnant patients to participate in the Mycophenolate Pregnancy Registry  Obtain a signed Patient-Prescriber Acknowledgment Form from females of reproductive potential  Explain how your center will address the risks of mycophenolate-related first trimester pregnancy loss and congenital malformations

Please note that the program manufacturers may contact you in the future for assessment of Mycophenolate REMS.

For more information about Mycophenolate REMS, including all program materials and instructions on how to enroll, please visit www.MycophenolateREMS.com or call 1-800-617-8191.

The FDA requests healthcare providers to report any pregnancies of which they become aware. Pregnancies that occur during treatment with mycophenolate or within 6 weeks following discontinuation of treatment should be reported by contacting the Mycophenolate Pregnancy Registry.  By phone: 1-800-617-8191  Online: www.MycophenolateREMS.com  Or by mail: Mycophenolate Pregnancy Registry 201 Broadway, Suite 5 Cambridge, MA 02139 Thank you for your commitment to helping patients understand the risks and benefits associated with mycophenolate treatment.

Sincerely,

Mycophenolate REMS Team

(Continued on next page)

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Indications and Important Selected Safety Information About Mycophenolate-Containing Products

INDICATIONS:

management of organ transplant recipients Mycophenolic acid is indicated for the prophylaxis of should prescribe mycophenolate- organ rejection in patients receiving allogeneic renal containing products. Patients receiving transplants, administered in combination with cyclosporine mycophenolate-containing products should and corticosteroids. be managed in facilities equipped and

staffed with adequate laboratory and CONTRAINDICATIONS: supportive medical resources. The

physician responsible for maintenance . Allergic reactions to mycophenolate-containing therapy should have complete information products have been observed; therefore, requisite for the follow-up of the patient. mycophenolate-containing products are

contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product.

. CellCept Intravenous is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).

(Continued on next page)

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Important Selected Safety Information About Mycophenolate-Containing Products (cont’d)

WARNINGS: Serious Infections Embryofetal Toxicity . Patients receiving immunosuppressants, including . Mycophenolate-containing products can cause fetal mycophenolate, are at increased risk of developing harm when administered to a pregnant female. Use bacterial, fungal, protozoal and new or reactivated of mycophenolate-containing products during viral infections, including opportunistic infections. pregnancy is associated with an increased risk of first These infections may lead to serious, including trimester pregnancy loss and an increased risk of fatal outcomes. congenital malformations, especially external ear and . Polyomavirus associated nephropathy (PVAN), JC other facial abnormalities including cleft lip and virus associated progressive multifocal palate, and anomalies of the distal limbs, heart, leukoencephalopathy (PML), cytomegalovirus esophagus, and kidney. (CMV) infections, reactivation of hepatitis B (HBV) Pregnancy Exposure Prevention and Planning or hepatitis C (HCV) have been reported.

. Females of reproductive potential must be made Neutropenia aware of the increased risk of first trimester . Severe neutropenia [absolute neutrophil count pregnancy loss and congenital malformations and 3 must be counseled regarding pregnancy (ANC) <0.5 x 10 /µL] developed in up to 2.0% of prevention and planning. renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving Lymphoma and Malignancy mycophenolate mofetil 3g daily. . Patients receiving immunosuppressive regimens involving combinations of drugs, including . Patients receiving mycophenolate-containing mycophenolate-containing products, as part of an products should be monitored for neutropenia. immunosuppressive regimen are at increased risk of . If neutropenia develops [absolute neutrophil count developing lymphomas and other malignancies, 3 particularly of the skin. (ANC) <1.3 x 10 /µL] or anemia occurs, dosing with mycophenolate-containing products should Combination with Other Immunosuppressive Agents be interrupted or the dose reduced, appropriate . Mycophenolate mofetil has been administered in diagnostic tests performed, and the patient combination with the following agents in clinical managed appropriately. trials: antithymocyte globulin, OKT3, cyclosporine, Pure Red Cell Aplasia and corticosteroids. . Cases of pure red cell aplasia (PRCA) have been . Mycophenolic acid has been administered in reported in patients treated with mycophenolate- combination with the following agents in clinical containing products in combination with other trials: antithymocyte/lymphocyte immunoglobulin, immunosuppressive agents. Patients receiving muromonab-CD3, basiliximab, daclizumab, mycophenolate-containing products should be cyclosporine, and corticosteroids. monitored for blood dyscrasias.

. The efficacy and safety of the use of mycophenolate-containing products, in combination with other immunosuppressive agents have not CAUTION: CELLCEPT INTRAVENOUS SOLUTION been determined. SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION

(Continued on next page)

IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Important Selected Safety Information About Mycophenolate-Containing Products (cont’d) Pregnancy Category D PRECAUTIONS: . Mycophenolate-containing products can cause Pregnancy Exposure Prevention and Planning fetal harm when administered to a pregnant . Females of reproductive potential* must be female. If mycophenolate-containing products made aware of the increased risk of first are used during pregnancy, or if the patient trimester pregnancy loss and congenital becomes pregnant while taking mycophenolate- malformations and must be counseled regarding containing products, the patient should be pregnancy prevention and planning. apprised of the potential hazard to the fetus. In certain situations, the patient and her healthcare . Females of reproductive potential taking practitioner may decide that the maternal mycophenolate-containing products must benefits outweigh the risks to the fetus. Risks receive contraceptive counseling and use and benefits of mycophenolate-containing acceptable contraception during entire therapy products should be discussed with the patient. with mycophenolate-containing products and for 6 weeks after stopping therapy (see Full . For those females using mycophenolate- Prescribing Information for acceptable containing products at any time during contraception methods). pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the . Patients should be aware that mycophenolate- healthcare practitioner should report the containing products reduce blood levels of the pregnancy to the Mycophenolate Pregnancy hormones in the oral contraceptive pill and could Registry (1-800-617-8191). The healthcare theoretically reduce its effectiveness. practitioner should also strongly encourage the patient to enroll in the pregnancy registry. . To prevent unplanned exposure during Gastrointestinal Disorders pregnancy, females of reproductive potential should have a serum or urine pregnancy test . Gastrointestinal bleeding (requiring with a sensitivity of at least 25 mIU/mL hospitalization) has been reported in de novo immediately before starting a mycophenolate- renal transplant patients (1.0%) and containing product. maintenance patients (1.3%) treated with mycophenolic acid (up to 12 months); and in . Another pregnancy test with the same sensitivity approximately 3% of renal, in 1.7% of cardiac should be done 8 to 10 days later. Repeat and in 5.4% of hepatic transplant patients pregnancy tests should be performed during treated with mycophenolate mofetil 3g daily. routine follow-up visits. . Mycophenolate-containing products should be . Results of all pregnancy tests should be administered with caution in patients with active discussed with the patient. serious digestive system disease because mycophenolate-containing products have been . In the event of a positive pregnancy test, associated with an increased incidence of females should be counseled with regard to digestive system adverse events. whether the maternal benefits of mycophenolate Concomitant Medications treatment may outweigh the risks to the fetus in certain situations. . It is recommended that mycophenolate- containing products not be administered . For patients who are considering pregnancy, concomitantly with azathioprine because of the consider alternative immunosuppressants with potential to cause bone marrow suppression and less potential for embryofetal toxicity. inhibit purine metabolism.

(Continued on next page) IMPORTANT DRUG WARNING Regarding Mycophenolate-Containing Products

Important Selected Safety Information About ADVERSE REACTIONS: Mycophenolate-Containing Products (cont’d) . The principal adverse reactions associated with . Caution should be used in the concomitant the administration of mycophenolate mofetil administration of mycophenolate-containing include diarrhea, leukopenia, sepsis, vomiting, products with drugs that interfere with and there is evidence of a higher frequency of enterohepatic recirculation such as certain types of infections, eg, opportunistic cholestyramine because of the potential to infections. Phlebitis and thrombosis have been reduce the efficacy of mycophenolate-containing reported with intravenous administration. products. . The principal adverse reactions associated with Immunizations the administration of mycophenolic acid include . During treatment with mycophenolate-containing constipation, nausea, and urinary tract infection in products, avoid the use of live attenuated de novo patients and nausea, diarrhea, and vaccines and advise patients that vaccinations nasopharyngitis in maintenance patients. may be less effective.

Phenylketonurics For additional safety information, please see full . Care should be taken if mycophenolate mofetil Prescribing Information, including Boxed oral suspension is administered to patients with WARNING and Medication Guide, which can be phenylketonuria. Complete blood counts should found at www.MycophenolateREMS.com. be performed weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year.

Nursing Mothers . It s not known whether mycophenolate-containing products are excreted in human milk. Because many drugs are excreted in human milk, and

because of the potential for serious adverse reactions in nursing infants from mycophenolate- containing products, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of

the drug to the mother.

. Patients should not breastfeed during mycophenolate-containing products therapy.

* A female of reproductive potential incudes girls who have entered puberty and all women who have a uterus and have not yet passed through menopause.

JOURNAL INFORMATION

IMPORTANT SAFETY INFORMATION FOR PRESCRIBERS OF MYCOPHENOLATE

Mycophenolate REMS (Risk Evaluation and Mitigation Strategy) has been mandated by the FDA (Food and Drug Administration) due to postmarketing reports showing that exposure to mycophenolate during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Mycophenolate is available by prescription as  CellCept® (mycophenolate mofetil)  Myfortic® (mycophenolic acid)  Generic formulations of mycophenolate mofetil  Generic formulations of mycophenolic acid

The goals of Mycophenolate REMS are 1. To prevent unplanned pregnancy in patients using mycophenolate and to minimize fetal exposure to mycophenolate by informing prescribers and females of reproductive potential about • The increased risks of first trimester pregnancy loss and congenital malformations associated with exposure to mycophenolate during pregnancy; and • The importance of pregnancy prevention and planning 2. To minimize the risks associated with fetal exposure to mycophenolate by collecting information on pregnancy outcomes through the Mycophenolate Pregnancy Registry 3. To inform patients about the serious risks associated with mycophenolate

What you need to know to prescribe mycophenolate

All prescribers of mycophenolate and females of reproductive potential, whether or not they plan to get pregnant, should participate in Mycophenolate REMS. Mycophenolate Pregnancy Registry It is important for healthcare providers to report any pregnancies of which they become aware that occur during treatment with mycophenolate or within 6 weeks following discontinuation of treatment. The Mycophenolate Pregnancy Registry has been established to evaluate mycophenolate-exposed pregnancies and their outcomes. Pregnancies should be reported by contacting the Mycophenolate Pregnancy Registry at 1-800-617-8191. Visit www.MycophenolateREMS.com or call 1-800-617 -8191 to access all resource materials.

For complete safety information, please see full Prescribing Information, including Boxed WARNING and Medication Guide, which can be found at www.MycophenolateREMS.com

OB/GYN CONTRACEPTION COUNSELING LETTER

Letter to Ob/Gyn Contraception Counseling ((Date))

((Recipient’s Name)) ((Recipient’s Address 1)) ((Recipient’s Address 2)) ((City, State, ZIP))

In reference to: My patient ((Patient’s Name)) Reason for the referral: Contraception counseling

Dear Dr ((Recipient’s Last Name)):

Prescribers of mycophenolate participate in the FDA-mandated Mycophenolate REMS (Risk Evaluation and Mitigation Strategy) to ensure that the benefits of mycophenolate outweigh the risks.

The following table lists the forms of contraception that are acceptable for use during treatment with mycophenolate.

Acceptable Contraception Methods for Females of Reproductive Potential Guide your patients to choose from the following birth control options:

Option 1  Intrauterine devices (IUDs)  Tubal sterilization Methods to Use  Patient’s partner had a vasectomy Alone OR Option 2 Hormone Methods Barrier Methods

choose 1 choose 1 Choose One Estrogen and Progesterone  Diaphragm with spermicide Hormone Method  Oral contraceptive pill  Cervical cap with spermicide AND One Barrier  Transdermal patch  Contraceptive sponge Method  Vaginal ring  Male condom AND Progesterone-only  Female condom  Injection  Implant

OR Option 3 Barrier Methods Barrier Methods

choose 1 choose 1 Choose One  Diaphragm with spermicide  Male condom Barrier Method  Cervical cap with spermicide  Female condom From Each AND Column (must  Contraceptive sponge choose two methods)

Patients should be aware that mycophenolate reduces blood levels of the hormones in the oral contraceptive pill and could reduce its effectiveness. An additional barrier method must be used with any hormonal contraceptives.

Patients should also be counseled on the availability of emergency contraception.

Unless patients choose not to have sexual intercourse with a man at any time (abstinence), they should be instructed to use acceptable birth control during the entire treatment with mycophenolate and for 6 weeks after they stop taking mycophenolate.

You can find more information about Mycophenolate REMS, including the roles and responsibilities of patients and prescribers of mycophenolate, at www.MycophenolateREMS.com. The site provides educational materials, as well as access to full Prescribing Information, Important Safety Information and Medication Guides for mycophenolate-containing products.

Please call me at ((Signatory’s phone)) at your earliest convenience. Thank you for your cooperation.

Sincerely,

((Signatory’s Name)) ((Signatory’s Practice))

CC10/11

OB/GYN PRECONCEPTION COUNSELING LETTER

Letter to OB/G Letter to Ob/Gyn Pre-conception counseling ((Date))

((Recipient’s Name)) ((Recipient’s Address 1)) ((Recipient’s Address 2)) ((City, State, ZIP))

In reference to: My patient ((Patient’s Name)) Reason for referral: Pre-conception counseling

Dear Dr ((Recipient’s Last Name)):

I am writing to you in reference to the above-named patient who is under my care for ((diagnosis)) and ((insert drug information such as drug name, when patient will begin taking the drug, if treatment has already begun, etc)). This medication contains mycophenolate, and the patient is considering a pregnancy. Because exposure to mycophenolate during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations, it is important that this patient receive pregnancy planning education. There are three components to pregnancy planning which include the following: 1. Pre-conception counseling 2. Determining whether there are appropriate treatment options with less potential for embryofetal toxicity 3. Optimizing the patient’s underlying medical conditions prior to conception

I would like you to provide pre-conception counseling in order to optimize the patient’s future pregnancy outcome. Although a decision regarding treatment options with less potential for embryofetal toxicity may not have been made at the present time, these discussions will be done by my practice.

Prescribers of mycophenolate participate in the FDA-mandated Mycophenolate REMS (Risk Evaluation and Mitigation Strategy) to ensure that the benefits of mycophenolate outweigh the risks.

You can find more information about Mycophenolate REMS, including the roles and responsibilities of patients and prescribers of mycophenolate, at www.MycophenolateREMS.com. The site provides educational materials, as well as access to full Prescribing Information, Important Safety Information, and Medication Guides for mycophenolate-containing products.

I look forward to working with you to ensure that this patient receives appropriate pregnancy planning education. ((Insert any further details specific to this patient that the OB/GYN should know.))

Please call me at ((Signatory’s phone)) at your earliest convenience. Thank you for your cooperation.

Sincerely,

((Signatory’s Name)) ((Signatory’s Practice))

MYCOPHENOLATE REMS HOMEPAGE