CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-024
`
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
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`
`
`

`

`
`
`
`
`DATE:
`
`TO:
`
`
`FROM:
`
` FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF METABOLISM AND ENDOCRINOLOGY PRODUCTS
`
`
`M E M O R A N D U M
`
`
`
`October 26, 2008
`
`ACTOPLUS MET XR (pioglitazone HCl plus metformin HCl extended release)
`(NDA 22-024)
`
`Mary H. Parks, M.D., Director, Division of Metabolism and Endocrinology
`Products (DMEP)
`Amy G. Egan, M.D., M.P.H., Deputy Director for Safety, DMEP
`
`
`
`SUBJECT: REMS requirement for ACTOPLUS MET XR
`
`
`
`This memorandum documents the basis for our decision to require a Risk Evaluation and
`Mitigation Strategy (REMS) for the ACTOPLUS MET XR NDA.
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the Federal Food, Drug, and Cosmetic Act (FDCA) to authorize FDA to
`require the submission of a Risk Evaluation and Mitigation Strategy (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)(1)). Section 505-1(a)(1) provides the following factors:
`
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to the drug
`and the background incidence of such events in the population likely to use the drug
`(F) Whether the drug is a new molecular entity.
`
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS is necessary for ACTOPLUS MET XR to
`ensure that the benefits of the drug outweigh the risks of heart failure associated with the use of
`pioglitazone-containing products, based on clinical trial data. In reaching this determination, we
`considered the following:
`
`
`

`

`A. Approximately 24 million people in the U.S. have diabetes, of whom more than one-third
`will require more than one anti-diabetic agent to maintain adequate glycemic control within
`several years of initiation of drug therapy. The potential market for ACTOPLUS MET XR is
`several million patients annually.
`
`
`B. Patients with type 2 diabetes who require more than one anti-diabetic agent for glycemic
`control are at risk for a variety of complications including heart disease, stroke, blindness,
`kidney failure, nervous system damage, amputations, and death if untreated. ACTOPLUS
`MET XR is an option for those individuals who are inadequately treated with anti-diabetic
`monotherapy.
`
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`C. The expected benefit of this combination drug product in terms of glycemic control is greater
`than either component administered as monotherapy.
`
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`D. The expected duration of therapy is over a patient’s lifetime.
`
`E. One of the drugs comprising ACTOPLUS MET XR, metformin, has been associated with
`various other adverse effects, including lactic acidosis. Additionally, in a long-term
`cardiovascular outcomes trial, 5238 patients were randomized to pioglitazone (n=2605) or
`placebo (n=2633) in addition to their background anti-diabetic medications. The percentage
`of patients who had a serious heart failure event was higher for patients treated with
`pioglitazone (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). In patients
`treated with an insulin-containing regimen at baseline, the incidence of serious heart failure
`was 6.3% (n=54/864) with pioglitazone and 5.2% (n=47/896) with placebo. For those
`patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious
`heart failure was 5.8% (n=94/1624) with pioglitazone and 4.4% (n=71/1626) with placebo.
`
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`F. ACTOPLUS MET XR contains metformin and pioglitazone and is not a new molecular
`entity.
`
`
`In accordance with section 505-1 of the FDCA, as one element of a REMS, FDA may require the
`development of a Medication Guide as provided for under 21 CFR Part 208. Pursuant to 21 CFR
`Part 208, FDA has determined that ACTOPLUS MET poses a serious and significant public
`health concern requiring the distribution of a Medication Guide. The Medication Guide is
`necessary for patients’ safe and effective use ACTOPLUS MET. FDA has determined that
`ACTOPLUS MET is a product that has serious risk (relative to benefits) of which patients
`should be made aware because information concerning the risk could affect patients’ decisions to
`use, or continue to use ACTOPLUS MET.
`
`The elements of the REMS will be Medication Guide and a timetable for submission of
`assessments of the REMS.
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`

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`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Julie Marchick
`1/28/2009 07:03:28 AM
`CSO
`
`Mary Parks
`1/28/2009 07:22:55 AM
`MEDICAL OFFICER
`
`