`CENTER FOR DRUG EVALUATION AND RESEARCH
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`Approval Package for:
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`APPLICATION NUMBER:
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`125166s172
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` Soliris
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`Eculizumab
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`Alexion Pharmaceuticals, Inc.
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`September 23, 2011
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`For the treatment of atypical hemolytic uremic syndrome
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`Trade Name:
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`Generic Name:
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`Sponsor:
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`Approval Date:
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`Indication:
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`125166s172
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`CONTENTS
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`Reviews / Information Included in this NDA Review.
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`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`125166s172
`APPROVAL LETTER
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`2'Food-zau’di'Drugr'Administration
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`.“Silver Spring -‘-'MD , 20993
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`Our STN: BL 125166/172
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`SUPPLEMENTAL: BLA ACCELERATED APPROVAL
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`REMS ASSESSMENT INCOMPLETE
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`REMS MODIFICATION APPROVAL
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`September 23, 2011
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`Alexion Pharmaceuticals, Inc.
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`Attention: Claude Nicaise, M.D.
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`Senior Vice President of Strategic Development
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`And Regulatory Affairs
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`352 Knotter Drive
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`Cheshire, CT 06410
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`Dear Dr. Nicaise:
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`Please refer to your Supplemental Biologics License Application (sBLA), dated March 25, 2011,
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`received. March 25, 2011, submitted under section 351 of the Public-Health Service Act for
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`'Soliris® (eculizurnab).
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`We acknowledge receipt-ofyour amendments dated April 5, 2011, April 25, 2011,
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`April 29, 2011, May 17, 2011, May 24, 2011, May 27, 2011, June 3, 2011, June 8, 2011,
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`June 9, 2011, June 10, 2011, July 19, 2011, July 20, 2011, and July 26,2011,and your risk
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`evaluation and mitigation strategy (REMS) assessment dated May 31, 2011.
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`This “Prior Approval” efficacy supplement to your biologics license application provides for the
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`treatment of atypical Hemolytic Uremic Syndrome (aHUS), as a secondindication for
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`Soliris®_(eculizmnab).
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`We have completed our review-of this supplemental application, as amended. It is approved,
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`effective on the date of this: letter, for use as recommended in the enclosed, agreed-upon labeling
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`'We.» also refer to your May 31, 201 1,. submission containing your assessment of the Soliris®
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`(eculizurnab) risk evaluation and- mitigation strategy (REMS). After consultation between the
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`Office of, Surveillance and Epidemiologyand the Office of New Drugs, we found the. REMS
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`assessment to be incomplete in that you did not submit patient and prescriber surveys. .In
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`=add1t10nthe assessment showed a lowrate ofprescriber enrollment1nto the REMS. Therefore,
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`~ mod1fications have been made to theREMS to increase prescriber enrollment.
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`Reference ID: 3168294
`Reference ID: 3168294
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`BL 125166/172
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`Page 2
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`CONTENT-n EL " ELING
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`'Within114 days of the:date.ofthis:letter,‘ submit content of labeling [21 CPR. 601 .14(b)]_. in
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`structured product. labeling (SPL) format,»as described at
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`,_ http://www.fda.gov/ForIndustry’lDataStandards/StructuredProductLabgling/defaulthtm that is
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`identical in content to the enclosed labeling text. The content of: labeling should be submitted by
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`updating your application by referencing the SPL file submitted to the drug establishment
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`registration and drug listing system. To. do this, place a link in your application submission that
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`directs FDA to your SPL file. For administrative purposes, please designate this submission
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`“Product Correspondence — Final SPL for approved STN BLA 125166/172.”
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`In addition, within 14 days of the date of this letter, amend any pending supplement(s). for this
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`BLA with content of labeling inSPL format to include the changes approved in this supplement.
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`For additional information on submitting labeling to drugestablishment registration and, drug
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`listing and to applications, see the FDA guidances at
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`cm072339.pdf and
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`ato Information/Guidances/u
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`CM072392.pdf,
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`ato Information/Guidances/U
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 35 So), all applications for new
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`Because this biological product for this indication has an orphan drug designation, you are
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`exempt from this requirement.
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`ACCELERATED APPROVAL REQUIREMENTS
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`As requested in your letter of March'25, 2011, marketing approval of this product is granted
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`under the accelerated approval of biological products regulations, 21 CFR 601.40-46. These
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`regulations permit the use of certain surrogate endpoints or an effect on a clinical endeint other
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`than survival or irreversible morbidity asbases for approvals of products intended for serious or
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`life-threatening illnesses or conditions.
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`Approval under these regulations requires, among other? things, that you conduct adequate and
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`well-controlled trials to verify and describe, clinical benefit attributable to this product. Clinical
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`benefit is evidenced by effects such as increased survival or improvement in'disease-related
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`symptoms. You are required toconduct such'trials with due diligence. ‘If postmarketing trials
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`fail to verify that clinical benefit is conferred by Soliris, or are» not conducted with duediligence,
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`we may, following a hearing in accordance with 21 CFR 601.43(b), withdraw or modify
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`approval. Granting of this approval is contingent upon completion of clinical trials to verify the
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`Reference ID: 3168294
`Reference ID: 3168294
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`BL 125166/172
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`Page 3
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`clinical benefit ofSoliris, as outlinedin your letterofSeptember 1,. 2011. Thesetrials are subject
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`to the reporting. requirements of 21 CFR 601.70:
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`1.
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`'PMR 172/1: An open—label, multi-center clinical trial of eculizumab in pediatric patients
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`with atypical hemolytic uremic syndrome. This trial will be amended to include
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`pharmacokinetic, efficacy and safety data from a minimum of five patients who are treated
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`with eculizumab in each of the following age cohorts:
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`5 to 12 years.
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`Final Protocol Submission. Date:
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`Trial Completion Date:
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`November 201 1
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`'PMR 172/2: An open-label, multi-center clinical trial of eculizumab in adult patients with
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`atypical hemolytic uremic syndrome. Thistrial will enroll a minimum of 30 patients.
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`June 2011
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`We expect you to complete design, initiation, accrual, completion, and reporting of these studies
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`' within the framework described in your letter of September 1, 2011.
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`For administrative purposes, all submissions related to these postmarketing trials should be
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`clearly designated f‘Subpart E Postmarketing Study Commitments”.
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`POSTMARKETING'RE UIREMENTS UNDER 505 0
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`Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
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`require holders of approved drug and biological product applications to conduct postmarketing
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`studies and clinical trials for certain purposes, if FDA makes certain findings required by the
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`Since Soliris®(eculizumab) was approved on March 16, 2007, we have become aware ofthe
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`serious risk of meningococcal and other infections with Soliris®(eculizumab), based upon
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`postmarketing information. Additionally,in patients with atypical hemolytic uremic syndrome,
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`thereIS a need to further assess the potential risk of secondary malignancies and ofpotential
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`information to be “new safety information” as defined1n section 505-l(b)(3) of the FDCA.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
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`under subsection 505(k)(1) of the FDCA will not be sufficient to assess the known risk of serious
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`infections, the serious- risks of secondary malignancies, and the- potential complications
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`Reference ID: 3168294
`Reference ID: 3168294
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`Page 4
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`associatedzwith-use of SOliris®(eculizumab). in: pregnancy. Furthermore, the.» new
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`:pharmacovigilance-= system thaté-FDA: is'required. to; establish undersection 5.05(k)(3)‘ of the
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`.FDCA. will) notbersufficient to. assess these-serious-risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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`conduct the following:
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`PMR 172/3: Evaluate the long-term safety of eculizumab by enrolling all patients with aHUS
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`treated with eculizumab in a Soliris registry program and analyzing outcomes for aperiod of no
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`less than five years. Submit interim reports annually to the'BLA including the specific items
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`listed below. At the. end of the five-year period, submit a final report to the BLA that describes
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`the major safety findings fromthis registry, including the specific items listed below, and
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`propose labeling changes as-appropriate. The followingdata will be collected for each patient
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`receiving eculizumab for the treatment of aHUS:
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`Serious infections, defined as infections necessitating or prolonging: hospitalization, or
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`resulting in death. Alexion will collect follow-up information from these patients to
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`assess the nature of the serious infection, the major features of the clinical course, and the
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`0 Malignancy, including the nature of the malignancy and the survival status of patients
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`Pregnancy, including the clinical course of each pregnancy and the detection of
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`congenital abnormalities among babies born to women exposed to eculizumab during the
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`Survival
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`0 Occurrence of stroke (yes/no)
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`0 New dialysis requirement or increase in the frequency of dialysis (yes/no)
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`- Discontinuation (yes/no) and, if discontinued, the reason for discontinuation.
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`The timetable you submitted on September 1, 2011 states that you will conduct this study
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`according to the following schedule:
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`' Final Protocol Submission: November 2011
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`Interim report:
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`Interim report:
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`Interim report:
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`Study Completion:
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`Final'Report Submission:
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`Reference ID: 3168294
`Reference ID: 3168294
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`Submit the. protocol: tozyourf IND :1 1075, with'atcross:-'reference'-~ letterto:thisi‘BLASSubmit all
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`.. final report(s)' to'your-F BLA. -‘ Prominently: identifysthesubmissionwith-the:following-{wording in
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`’bold. capital: letters-at: .the top- of,therifirst: page: ()fithexsubmission,~ as-appropriater ‘fReq-uire‘d
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`f'PostmarketingProtocol- Underf505(o)”,' “Required PostmarketingT‘Final?Report-Under
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`Section 505(0)(3)(E)(ii) oftheIFDCA requires you to- report periodically on the status of any
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`study or clinical trial" required under this section. This-section also requires you to: periodically
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`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
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`safety issue. Section 506B of the FDCA, as well as 21 CFR 601.70 requires you to report
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`annually on the status of any postmarketing commitments or required studies or clinical trials.
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`FDA will, consider the submission of your. annual reportunder section 506B and 21 .CFR 601.70
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`to satisfy the-periodic reporting requirementunder section 505(0)(3)(E)(ii) provided that you
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`include the elements listed in 505(0) and 21 CFR 60170. We remind you that to comply with
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`505(0), your. annual report must also include a report on the status of any study or clinical trial
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`otherwise undertaken to investigate a safety issue. Failure to submit anannual report for studies
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`or clinical trials required under 505(0) onéthe date-required will be considered a violation of
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`FDCA section 505(0)(3)(E)(ii) and could-resultin. enforcement action.
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`RISK EVALUATION AND MITIGATION STRATEGY'RES [UIREMENTS
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`The REMS for Soliris®(eculizumab) was originally approved on June 4,2010. The REMS
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`consists of a’ Medication Guide, elements to assure safe use, and a timetable for submission of
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`assessments of the REMS. Your proposed modifications to the REMS consist of revisions to the
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`REMS document, Medication Guide, and appended REMS materials. These modifications are to
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`provide consistency with the revised package insert and to revise the REMS document and the
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`REMS materials to facilitate prescriber certification in the REMS.
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`Your proposed modified REMS, submitted on September 19, 2011, as amended, and appended
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`to this letteris approved.
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`The timetable for submission of assessments of the REMS will remain the same as approved on
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`The revised REMS assessment plan should include, but is not limited to, the following:
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`1. Assessment of enrollment and discontinuation statistics forpatients and prescribers
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`o The number of. patients enrolledain- the OneSource SafetySupport‘ Program. and
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`receiving Soliris treatment (during the reporting period and cumulative)
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`The number'of: patient person-years for enrolled patients on~Soliris
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`The number'of new patients enrolled during: the reporting: period
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`.The number ofpatients who- received Soliris Who were. not enrolled (during the
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`Reference ID: 3168294
`Reference ID: 3168294
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`

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`BL 125166/172
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`'Page 6
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`o The number ofpatients-‘who. discontinued Soliris (during. the- reporting. period: and
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`o The number ofpatients who were lost to follow up (during the reporting'period
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`and cumulative)
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`o Prescriber enrollment:
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`I Numbers enrolled: total and newly enrolled during the reporting period,
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`I Number who are prescribing Soliris who are not enrolled
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`0 Reasons that prescribers did not enroll
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`0 Actions taken to ensure that all prescribers are enrolled
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`2. An assessment of the following use. data for Soliris
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`o The number of patients treated by diagnosis
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`0 The percent of patients receiving meningococcal vaccination
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`3. The number and summary ofprescribers who were un-enrolled from the OneSource
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`Safety Support Program during the reporting period and cumulatively.
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`4. A narrative summary and analysis of meningococcal infections during the reporting
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`period; this will include for each case:
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`0 The serotype of Neisseria meningitides
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`o The type and timing of vaccination and revaccination against Neisseria
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`o The circumstances under which the patient sought/received treatment for
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`meningococcal infection, including the patient’s use of the Soliris Patient Safety
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`0 The clinical course of the meningococcal infection, and the outcome of the
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`5. An assessment of prescriber and patient understanding regarding the safe use of
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`Soliris i.e., the results of surveys administered to prescribers and patients.
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`6. Medication Guide distribution data, including the number of Medication Guides
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`dispensed in comparison to’the number of prescriptions shipped during the reporting
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`period, a report on periodic assessments of the distribution and dispensing of the
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`Medication Guide in accordancewith 21 CFR208.24, a report on failures to adhere to
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`distribution and dispensing requirements, and correctiveactions taken to address
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`noncompliance.
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`7. Based on the information submitted, an assessment of and conclusion regarding
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`whether the REMS is meeting its goals, and whether modifications to the REMS are
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`needed.
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`Reference ID: 3168294
`Reference ID: 3168294
`
`

`

`BL 125166/172
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`Page 7
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`‘8.
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`Additionally,»submit 'by March 1,1201 2,: a report on your'progress on; increasing
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`:1prescriber: enrollment. Thisreport shouldsinclude the'following data as of 120 days
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`following; approval of the.” REMS:- modification:
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`0 Numbers of prescribers enrolled: total enrolled and newly enrolled during the '120
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`days following approval of the REMS. modification.
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`0 Number who are prescribing Soliris who are not enrolled
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`0 Reasons that prescribers did not enroll
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`0 Actions taken to ensure that allprescribers are enrolled
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`An assessment of the extent to which the elements to assure safe use are meeting the
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`goal or goals to mitigate aspecific serious risk listed in the labeling of the drug, or
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`whether the, goal or goals or such elements should be modified;
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`10.
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`Information on the status of any postapproval study or clinical trial required under
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`section 505(0) or otherwise undertaken to investigatea safety issue. With respect to
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`any such postapproval study, you must include the status of such study, including
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`whether any difficulties completing the study. have been encountered. With respect to
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`any such postapproval clinical trial, you must include the status of such clinical trial,
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`including whether enrollment has begun, the. number of participants enrolled, the
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`expected completion date, whether. any difficulties completing the clinical trial have
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`been encountered, and registration information with respect to requirements under
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`subsections (i) and (j) of section 402 of the Public Health Service Act. You can
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`satisfy these requirements in your REMS assessments by referring to relevant
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`information included in the most recent annual report required under section 506B
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`and 21 CFR 21 CFR 601.70 and including any material or significant updates to the
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`status information since the annual report was prepared. Failure to comply with the
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`REMS assessments provisions in section 505-1(g) could result in enforcement action.
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`In addition to the assessments submitted according to the timetable included in theapproved
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`REMS, you must submit a REMS assessment and may propose a modification to the approved
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`REMS when you submit a supplemental application 'for a new indication for use as described in
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`section 505-1(g)(2)(A) of FDCA.
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`Prominently identify the submission containing the REMS assessments or proposed
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`modifications of the REMS with the following wording in bold capital letters at the top of the
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`first page of the submission as appropriate:
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`,
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`-BLA 125166‘REMS ASSESSMENT
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`NEW SUPPLEMENT FOR BLA 1125166
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`"PROPOSED-REMS MODIFICATION
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`REMS ASSESSMENT
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`Reference ID: 3168294
`Reference ID: 3168294
`
`

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`BL 125166/172
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`Page? 8
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`‘NEWxSUPPLEMENT (NEW?INDICATIONiFORiUSE)
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`:2FOR'EBLAi-l325166
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`REMS ASSESSMENT
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`r-PROPOSED'REMS MODIFICATION (if included)
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`PROMOTIONAL MATERIALS
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`You may request, advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
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`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
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`Food and Drug Administration
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`>
`Center for Drug Evaluation and Research
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`Division of Drug Marketing, Advertising, and Communications
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`You must submit final promotional materials, and the package insert, at the time of initial
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`dissemination or publication, accompanied by a Form FDA 2253. For instruction on completing
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`the Form FDA 2253, see page 2 of the Form. For more information about submission of
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`promotional materials to the Division of Drug Marketing, Advertising, and Communications
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`(DDMAC), see http://www.fda.gov/AboutFDA/CentersOffices/CDEqucm090142.htm.
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`All promotional claims must be consistent with and not contrary to approved labeling. You
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`should not make a comparative promotional claim or claim of superiority over other products
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`unless you have substantial evidence to support that claim.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved BLA (in
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`21 CFR 600.80 and in 21 CFR 600.81).
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`‘ We request expedited reporting (15 day telephone or facsimile Medwatch communication) for
`the occurrence of serious infections, including those identified in the Soliris®(eculizumab)
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`registry program.
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`Reference ID: 3168294
`Reference ID: 3168294
`
`

`

`BL 125166/172
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`Page 9
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`'If you‘ have any questions, contactthe’SeniorlRegulatoryiProject“Manager, Ebla Ali Ibrahim; at
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`(301') 796-3691.
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`Sincerely,
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`W99
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`/Ann T. Farrell M.D/
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`Ann ..T Farrell, M.D.
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`Acting Division Director
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`Division of Hematology Products
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`Office of Hematology Oncology Products
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`Center for Drug Evaluation and Research
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`Enclosure
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`Content of Labeling
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`REMS
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`Reference ID: 3168294
`Reference ID: 3168294
`
`

`

`
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`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`
`125166s172
`LABELING
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`

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`Prospective clinical trials in additional patientsare ongoing to
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`confirm the benefit of Soliris in patientswith aI-IUS.
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`W S
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`oliris is not indicated forthe treatment of patients with Shiga toxin E. coli
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`» related hemolytic uremic syndrome (STEC-l-IUS).
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`*DOSAGE AND ADMINISTRATION
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`Only administer as an intravenous infusion
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`PNl-I Dosage Regimen: (2.1)
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`aHUS Dosage Regimen: (2.2)
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`DOSAGE FORMS AND STRENGTHS
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`300 mg single-use vials each containing 30 mL of 10 mg/mL sterile,
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`preservative-free solution (3).
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`CONTRAINDICATIONS
`Soliris is contraindicated in:
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`0
`Patients with unresolved serious Neisseria meningitidis infection
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`(4).
`Patients who are not currently vaccinated against Neisseria
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`meningitidis, unless the risks of delaying Soliris treatment
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`outweigh the risks of developing a meningococcal infection (5.1).
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`c ‘
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`o
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`0
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`WARNINGS AND PRECAUTIONS
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`Discontinue Soliris in patients who are being treated for serious
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`meningococcal infections.
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`Use caution when administering Soliris to patients with any other
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`systemic infection (5.2).
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`ADVERSE REACTIONS
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`The most frequently reported adverse reactions in the PNH randomized trial
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`(210% overall and greater than placebo) are: headache, nasopharyngitis, back
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`pain, and nausea (6.1).
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`The most frequently reported adverse reactions in aHUS single arm
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`prospective trials (215% combined per patient incidence) are: hypertension,
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`upper respiratory tract infection, diarrhea, headache, anemia, vomiting,
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`nausea, urinary tract infection, and leukopenia (6.1).
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`USE IN SPECIFIC POPULATIONS
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`Pregnancy: Based on animal data, Soliris may cause fetal harm (8.1).
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`Nursing Mothers: Caution should be exercised when administered to a nursing
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`woman (8.3).
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`Pediatric Use: PNI-I: safety and effectiveness not established. aHUS: safety
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`and efi‘ectiveness similar to adult patients (8.4).
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`To report SUSPECTED ADVERSE REACTIONS, contact Alexion
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`Pharmaceuticals, Inc. at 1.888-SOLIRIS 0-888-765-4747) or FDA at 1-
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`800-FDA-1088 or w.fda.gov/medwatch.
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`These highlights do not include all the information needed to use-Soliris
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`safely-and effectively. ‘See full prescribing informationifor Soliris.
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`" Soliris® (eculizumab)
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`Concentrated solution for intravenous infusion
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`WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
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`Seefullprescribing informationfor complete boxed warning
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`Life-threatening and fatal meningococcal infections have occurred in
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`patients treated with Soliris.’ Meningococcal infection may become
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`rapidly life-threatening or fatal if not recognized and treated early (5.1).
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`Comply with the most current Advisory Committee on
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`Immunization Practices (ACIP) recommendations for
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`meningococcal vaccination in patients With complement
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`Immunize patients with a meningococcal vaccine at least 2
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`weeks prior to administering the firSt dose of Soliris,- unless the
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`risks of delaying Soliris therapy outweigh the risks of
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`developing a meningococcal infection. (See Serious
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`Meningococeal Infections (5.1) for additional guidance on the
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`management of the risk of meningococcal infection.)
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`Monitor patients for early signs of meningococcal infections,
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`and evaluate immediately if infection is suspected.
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`. Soliris is available only through a restricted program under a Risk
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`Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS
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`prescribers must enroll in the program (5.2). Enrollment in the Soliris
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`REMS program and additional information are available by telephone:
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`l-888-SOLIRIS 1-888-765-4747 .
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`—-—— RECENT MAJOR CHANGES
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`Box Warning
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`ndications and Usage (1.2)
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`Contraindications
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`Dosage and Administration (2.2)
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`Warnings and Precautions (5.3, 5.4 and 5.6)
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`Adverse Reactions (6.1)
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`Use in Specific Populations (8.4)
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`Clinical Studies (14.2)
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`Patient Counseling Information (17)
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`9/2011
`9/2011
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`INDICATIONS AND USAGE
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`Soliris is a complement inhibitor indicated for:
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`The treatment ofpatients with paroxysmal nocturnal
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`hemoglobinuria (PNH) to_ reduce hemolysis (1.1).
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`The treatment of patients with atypical hemolytic uremic syndrome
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`(aHUS) to inhibit complement-mediated thrombotic
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`microangiopathy (1.2).
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`See 17 PATIENT COUNSELING INFORMATION and the FDA-
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`The effectiveness of SolirisIn aHUS'Is based on the effects on
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`approved Medication Guide.
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`thrombotic microangiopathy (TMA) and renal function.
`Revised: 09/2011
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`INDICATIONS AND USAGE
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`Paroxysmal Noctumai Hemoglobinuria (PNI-i)
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`Atypical Hemolytic Uremic Syndrome (aHUS)
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`DOSAGE AND ADMINISTRATION
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`Recommended Dosage Regimen - PNH
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`Recommended Dosage Regimen - aHUS
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`Preparation and Administration
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`Administration
`DOSAGE FORMS AND STRENGTHS
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`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
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`Serious Meningococcal Infections
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`1
`1.1
`_ 1.2
`2
`2.1
`2.2
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`2.4
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`5
`5.1
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`5.2
`5.3
`5.4
`5.5
`5.6
`5.7
`6
`6.1
`6.2
`6.3
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`8
`8.1
`8.3
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`Soliris REMS .
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`Other Infections
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`Monitor