CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`202107Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`RISK MANAGEMENT REVIEW
`
`
`
`
`
`
`
`
`
`Date:
`
`Risk Management Analyst: Suzanne Robottom, Pharm.D.
`Division of Risk Management (DRISK)
`
`January 27, 2012
`
`
`Team Leader:
`
`Division Director:
`
`Drug Name:
`
`Dosage and Route:
`
`Application Type/Number: NDA 202-107
`
`
`
`
`
`Applicant/sponsor:
`
`Corcept
`
`OSE RCM #:
`
`
`
`
`
`
`
`
`
`
`Cynthia LaCivita, Pharm.D., DRISK
`
`Claudia Karwoski, Pharm.D., DRISK
`
`Korlym (mifepristone)
`
`300 mg tablets; by mouth
`
`
`
`2011-2351
`
`
`
`
`Reference ID: 3078677
`
`

`

`EXECUTIVE SUMMARY
`The purpose of this review is to document DRISK’s determination that a risk evaluation
`and mitigation strategy (REMS) with elements to assure safe use (ETASU) is not
`necessary for the approval of mifepristone for the treatment of the signs and symptoms of
`endogenous Cushing’s syndrome.
`Corcept submitted a 505(b)(2) application for approval of Korlym (mifepristone) for the
`treatment of the signs and symptoms of endogenous Cushing’s syndrome. Mifepristone
`(Mifeprex) is currently approved for pregnancy termination with a REMS with ETASU.
`Based on FDA feedback provided at the September 14, 2010 pre-NDA meeting, Corcept
`proposed a REMS with ETASU with their NDA submission.
`After extensive research and multiple discussions with the review team, DRISK and the
`Division of Metabolism and Endocrinology Products (DMEP) determined that:
` A REMS with ETASU is not necessary to ensure that the benefits outweigh the
`risks of Korlym in the Cushing’s population.
` A REMS with ETASU for Korlym would not improve the benefit/risk balance for
`the intended use (Cushing’s) population and would add burden.
` Use of Korlym outside of Cushing’s syndrome cannot be prospectively
`quantified.
`The REMS Oversight Committee and the Center Director provided additional guidance
`and affirmed that although a REMS is required for Mifeprex, a REMS for Korlym is not
`necessary to ensure that the benefits of the drug outweigh its risks at this time. Korlym’s
`safety and drug utilization should use be monitored through post marketing requirements
`(PMR). If data indicate that the current approach compromises the integrity of the
`Mifeprex REMS and results in serious adverse events, or additional serious safety signals
`arise, further regulatory action must be considered.
`
`1
`INTRODUCTION
`The purpose of this review is to document DRISK’s determination that a REMS with
`ETASU is not necessary for the approval of mifepristone for the treatment of the signs
`and symptoms of endogenous Cushing’s syndrome.
`
`1.1 BACKGROUND
`Corcept submitted a 505(b)(2) application on April 15, 2011 for approval of Korlym
`(mifepristone) to treat the clinical and metabolic effects of hypercortisolism in adult
`patients (≥ 18 years of age) with endogenous Cushing’s syndrome including:
` Patients with Cushing’s disease who have not adequately responded to or relapsed
`after surgery
` Patients with Cushing’s disease who are not candidates for surgery
`
`
`
`Reference ID: 3078677
`
`2
`
`(b) (4)
`
`

`

`Korlym is manufactured as 300 mg tablets. The proposed dosing for the aforementioned
`indication is 300 to 1200 mg daily by mouth.
`
`1.2 REGULATORY HISTORY
`Mifepristone if currently marketed as Mifeprex and approved on September 28, 2000
`under 21 CFR 314 Subpart H for the medical termination of intrauterine pregnancy
`through 49 days’ pregnancy. The approved dosing is 6001 mg (three (3), 200 mg tablets)
`followed by misoprostol on Day 4. Since approval, mifepristone is available only through
`a restricted distribution program that requires prescribers to be enrolled to be able to
`order Mifeprex and should only be distributed to/through a clinic, medical office, or
`hospital, by or under the supervision of a specially certified prescriber. Mifeprex is not
`distributed to or dispensed through retail pharmacies. The restricted distribution program
`was approved as a REMS on June 8, 2011.2
`In 2007, Corcept initiated a clinical development program to evaluate the clinical benefit
`of mifepristone in patients with Cushing’s syndrome and received orphan drug
`designation on July 5, 2007.
`
`A pre-NDA meeting with Corcept was held on September 14, 2010. Corcept informed
`the FDA that they intended to submit a REMS and requested comments on the draft
`REMS. The FDA informed Corcept that for this NDA/indication, a REMS with restricted
`distribution would be necessary to address the risk of termination of pregnancy. The
`proposed REMS must be sufficient to maintain the integrity of the current Mifeprex
`restricted distribution program. The sponsor was instructed that a complete review of the
`proposed REMS, and REMS materials would be done in conjunction with the full clinical
`review after the NDA is submitted.
`
`On April 15, 2011 Corcept submitted NDA 202107 for review with a proposed REMS.
`
`2 MATERIALS REVIEWED
`
`The following materials were reviewed:
`
`
` Weber J. Pre-NDA Meeting Preliminary Comments for September 14, 2010.
`Signed under IND 76480 on September 9, 2010 by Weber J.
` NDA 202107 submitted on April 15, 2011 and received on April 18, 2011 with a
`proposed REMS with ETASU.
` Bhatnagar U. Maternal Health Team review for Mifepristone. Signed September
`15, 2011 by Bhatnagar U, Feibus K, and Mathis L.
` Greene P. Drug use review of Mifeprex. Signed September 19, 2011 by Greene P,
`Chai G, and Governale L.
`
`
`1 Standard practice is to dispense a single, 200 mg tablet of mifepristone, not 600 mg. In addition, the
`standard misoprostol dose is 800μg (4 tablets), not 400 μg.
`2 Mifepristone was included on the list of products deemed to have in effect an approved risk evaluation
`and mitigation strategy (REMS) under section 505-1 of the Federal Food, Drug, and Cosmetic Act with the
`passage of the Food and Drug Administration Amendments Act (FDAAA) of 2007.
`
`
`
`Reference ID: 3078677
`
`3
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`

`

` November 3, 2011 Center Director Briefing on Mifepristone for Cushing’s
`syndrome. Signed into DAARTS for NDA 202107 on November 15, 2011 by
`Egan A.
` Division of Reproductive and Urology Products consult response.
`Signed November 18, 2011 by
`.
`
`
`
`3 RISK BENEFIT CHARACTERIZATION
`
`3.1 CUSHING’S SYNDROME AND TREATMENT OPTIONS
`Cushing’s syndrome is a serious, multisystem disorder that results from overproduction
`of cortisol by the adrenal glands. For those not cured by surgery, it is a chronic and
`debilitating condition.4 If left untreated, Cushing’s syndrome limits survival to 4 to 5
`years following initial diagnosis.3
`
`Surgical resection of the offending tumor remains first line treatment, and initial cure or
`remission is obtained in 65-85% of patients with Cushing’s disease.4 In cases that surgery
`only partially or temporarily controls glucocorticoid hypersecretion (or for patients who
`are not candidates for surgery),5 radiation and/or pharmacologic treatment is used for
`disease control. A two to three fold increase in mortality is observed in most studies and
`this excess mortality seems confined to patients in whom initial cure was not obtained
`(the indicated population for mifepristone). 4
`
`There is an unmet medical need for additional drug treatment options for Cushing’s
`syndrome. The following table lists the drug treatment options, none of which are
`approved for Cushing’s syndrome:2,6
`
`
`Steriodogenic inhibition
`
`Adrenolytic
`
`Glucocorticoid
`receptor antagonism
` Mifepristone
`
`Neuromodulators
`of ACTH release
` Cyproheptidine*
` Metyrapone (not
`available in US)
` Bromocriptine*
` Aminoglutethimide
` Valproic acid*
`(discontinued)^
` Octreotide*
` Ketoconazole
`
`^Aminogluthethimide was approved in 1980 and indicated “for the the suppression of adrenal
`function in selected patients with Cushing’s syndrome.”
`^^Mitotane was approved in 1970 and indicated for “the treatment of inoperable adrenal cortical
`carcinoma of both functional and nonfunctional types.”
`*Agent has not demonstrated consistent clinical efficacy.3
`
`3 Gums JG, Smith JD. Adrenal Gland Disorders. Pharmacotherapy: A pathophysiologic approach. 4th ed.
`Ed Dipiro JT. Stamford, Appleton & Lange, 1999. Print.
`4 Steffensen C, Bak AM, Rubeck KZ, Jorgensen JO. Epidemiology of Cushing’s syndrome.
`Neuroendocrinology 2010;92(supp 1):1-5.
`5 Johanssen S. Allolio B. Mifepristone (RU 486) in Cushing’s syndrome. Euro J Endocrin (2007)156; 561-
`569.
`6 Heyn J, et al. Medical suppression of hypercortisolemia in Cushing’s syndrome with particular
`consideration for etomidate. Pituitary (online May 10, 2011).
`
` Mitotane^^
` Etomidate
`
`
`
`
`Reference ID: 3078677
`
`4
`
`(b) (6)
`
`(b) (6)
`
`

`

`
`
`3.1.1 Size of Population
`Cushing’s syndrome is a rare disorder with incidence ranging from 0.7 to 2.4 per 1
`million persons per year.7 Ninety percent of all cases of Cushing’s syndrome occur
`during adulthood; the incidence of Cushing’s syndrome in children is estimated at
`approximately 0.2 cases per 1 million persons per year.
`It is estimated that at any given time there are approximately 20,000 patients with
`Cushing’s syndrome in the U.S. The peak incidence of Cushing’s syndrome due to an
`adrenal or pituitary tumor occurs in persons 25-40 years of age; females are 8 times more
`likely than males to develop hypercortisolemia from a pituitary tumor and 3 times more
`likely to develop a cortisol-secreting adrenal tumor.
`In the US, it is estimated that approximately 5,000 patients would be considered
`candidates for treatment with Korlym.
`
`3.2 EXPECTED DRUG BENEFIT
`
`Mifepristone works by binding to glucocorticoid receptors, preventing cortisol from
`binding, and thereby blocking cortisol’s activity and effects. It does not decrease the
`amount of circulating cortisol. It has a rapid onset of action (~90 minutes for peak plasma
`concentrations).
`
`According to the sponsor in Study 400 (open label, 24 week prospective trial), 60% of the
`diabetes patients met the primary endpont of at least a 25% reduction in AUCglucose, and
`antidiabetic medication use was reduced in half of the patients. The Data Review Board
`determined that 72% of patients met the secondary endpoint of a change in signs and
`symptoms at week 24.
`
`Mifepristone may be used as an adjunct to radiation, palliative treatment, or when rapid
`onset of anti-glucocorticoid effect is required (e.g., psychosis).
`
`3.3 DURATION OF TREATMENT
`Cushing’s syndrome that is not cured by surgery is a chronic condition. Patients may be
`treated indefinitely (weeks, months, years/decades) with mifepristone.
`
`3.4 SEVERITY OF THE RISK
`The observed risks (adverse events documented in the safety database; adrenal
`insufficiency, hyopkalemia, and endometrial hyperplasia) in patients with Cushing’s
`syndrome were considered. After discussion with DMEP, we agree that these risks can be
`adequately addressed through labeling.
`
`
`
`7 Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006 May 13;367
`(9522):1605-17.
`
`
`
`Reference ID: 3078677
`
`5
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`

`

`Two risks were identified that are anticipated to occur in the post-marketing setting.
`These risks were the focus of the risk management discussion.
`
`3.4.1 Fetal Loss (unintended pregnancy termination)
`
`3.4.1.1 Cushing’s Syndrome Patients
`Mifepristone blocks progesterone receptors at lower doses than necessary for
`glucocorticoid receptor inhibition. Therefore, the lowest treatment dose studied for the
`treatment of Cushing’s syndrome is effective for terminating pregnancy. However,
`mifepristone alone is less effective for pregnancy termination when compared to the
`combined regimen mifepristone/prostaglandin.8
`
`
`Women with Cushing’s syndrome are not at substantial risk for fetal loss because they
`are unlikely to be pregnant. The review by the Maternal Health Team (MHT) states that
`amenorrhea and ovulatory disturbances are associated with untreated Cushing’s
`syndrome and therefore pregnancy occurs “rarely” in this population. Pregnancy may
`occur in a small subset of patients with Cushing’s syndrome who are of childbearing age.
`MHT recommends that this possibility be noted in labeling.9
`
`At the time treatment is initated with mifepristone, a woman has a low likelihood of
`conception due to her underlying disease. During treatment, if she is not compliant with
`mifepristone treatment, she would be amenorrheic due to worsened disease condition. If
`she is compliant with medication, mifepristone would prevent a sustained pregnancy.
`Therefore, the risk of fetal loss before and during treatment in the intended patient
`population appears low.
`
`Pregnancy tests were performed in Study 400 as part of enrollment and repeated after any
`significant interruption of treatment. No pregnancies were reported.
`
`3.4.1.2 Non-Cushing’s Syndrome Patients
`There are a variety of uses for mifepristone
`studied to treat the following:
`
`. It has been
`
`
`8
` Division of Reproductive and Urology Products consult response. Signed November 18, 2011 by
`.
`9 Bhatnagar U. Maternal Health Team review for Mifepristone. Signed September 15, 2011 by Bhatnagar U, Feibus K,
`and Mathis L.
`
`
`
`
`.
`
`
`
`Reference ID: 3078677
`
`6
`
`(b) (4)
`
`(b) (6)
`
`(b) (6)
`
`(b) (4)
`
`(b) (4)
`
`

`

`At present, mifepristone is only commercially available in blister packages (3 pills per
`carton) that are sold through the Mifeprex REMS. If Korlym is approved without
`restrictions (e.g. REMS), mifepristone will be more readily available to treat females of
`child bearing potential with other chronic conditions. The extent of off-label use of
`mifepristone, for the above conditions, in the post-marketing setting is unknown.
`
`3.4.2 Intended Termination of Pregnancy with Korlym
`If Korlym is approved without a REMS with restricted distribution, there will be
`increased access to mifepristone. This could lead to 1) prescribers prescribing Korlym for
`the termination of pregnancy without following the safeguards that are in place for
`Mifeprex and/or 2) misuse, pilfering, and diversion of Korlym for the termination of
`pregnancy not under the supervision of a healthcare provider.
`
`The risk mitigation tools for the Mifeprex REMS are physician certification and
`controlled access to assure safe use. A Mifeprex prescriber must agree that he/she meets
`the required qualifications to assure the drug is used safey and appropriately. Compliance
`with the REMS requirements is not enforced beyond a one-time completion of the
`enrollment form (e.g., signed Patient Agreements are not collected). The certification
`requirement is the tool that provides controlled access for Mifeprex. Without restricted
`distribution, a prescriber using Korlym for pregnancy termination would not have to
`attest to having certain skills, agree to document certain information/activities, or report
`adverse events. The patient would not receive a Patient Agreement or Mifeprex
`Medication Guide that would provide the most relevant and important information to her
`for pregnancy termination. The current REMS does not prevent use beyond 49 days
`gestation, termination of an ectopic pregnancy, bleeding, incomplete abortion, and
`infection.
`
`In considering if there is increased potential for pilfering and misuse with Korlym, we
`note that Mifeprex is distributed only to medical facilities and dispensed to the patient in
`small quantities (a single tablet) by certified prescribers. Korlym will be distributed
`directly to patients, in larger quantities and each Korlym tablet is an effective dose for
`pregnancy termination. Moreover, Korlym is proposed to be packaged in bottles of 28
`and 280, making diversion and pilfering presumably easier relative to the Mifeprex
`packaging. Similar to Korlym, there is potential for Mifeprex to be pilfered or diverted
`from a distribution facility, during shipping, or at the place of dispensing. Mifeprex has
`processes in place to prevent drug loss during distribution and shipping that can be done
`outside a REMS for Korlym. It is not known if clinics keep careful stock and dispensing
`records of Mifeprex.
`
`3.5 RISK IN CONTEXT OF DRUGS IN CLASS AND AMONG OTHER DRUGS USED TO
`TREAT THE DISEASE
`There are no other glucocorticoid receptor antagonists approved in the U.S. for
`comparison.
`Ketoconazole, metapyrone (not approved in U.S.), mitotane, etomidate are anti-corticolic
`drugs that are used for the treatment of Cushing’s syndrome. Because these drugs have a
`
`
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`Reference ID: 3078677
`
`7
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`

`

`different mechanism of action, they are not associated with the same potential risks as
`mifepristone. These drugs are associated with serious risk(s) although none of these drugs
`have a REMS.
`
`3.6 HOW THE RISK(S) ARE MANAGED ACROSS OTHER PRODUCTS AND/OR DISEASES
`
`3.6.1 Fetal Loss
`Other drug products are associated with fetal loss (e.g., methotrexate, misoprostol; see
`Attachment 1). At present, this risk is addressed through labeling for these drugs. There
`are no REMS approved that address only fetal loss without also the accompanying risk of
`birth defect.
`
`3.6.2 Intended Termination of Pregnancy with Korlym
`We identified two drugs, misoprostol and methotrexate, that are associated with a risk of
`pregnancy termination and are approved for other uses. See the table in Attachment 1.
`The extent to which misoprostol and methotrexate are used off-label to terminate
`pregnancy is unknown. With each drug, the risk of termination of pregnancy is managed
`through labeling (Contraindication, Boxed Warning) and neither product has a REMS.
`
`3.6.3 Misuse
`Misuse has been addressed in different ways as follows:
`Voluntary Restricted Distribution:
` Example: Egrifta/growth hormone: Growth hormones are at risk for misuse and
`abuse. None of the growth hormone products have a REMS. However, the sponsor
`has voluntarily decided to distribute this product through a non-REMS restricted
`distribution system which allows tracking “of each box of Egrifta to determine the
`volume of product dispensed and evaluate if the projected number of boxes dispensed
`correlates with prescription use in the intended population.”10 Egrifta was approved
`in 2010 with no REMS and no PMR for monitoring drug use.
`Required Restricted Distribution Program
` Example: Xyrem11
`o At the time Xyrem was initially approved in 2002, the Sponsor agreed as a
`condition of approval to distribute and dispense Xyrem through a primary and
`exclusive central pharmacy, implement a program to educate physicians and
`patients about the risks and benefits of Xyrem, fill the initial prescription only
`after the prescriber and patient received and read the educational materials, and
`maintain patient and prescribing physician registries.12
`
`
`10 LaCivita C. Review of REMS for Egrifta. Signed September 3, 2010.
`11 Xyrem was included on the list of products deemed to have in effect an approved risk evaluation and
`mitigation strategy (REMS) under section 505-1 of the Federal Food, Drug, and Cosmetic Act with the
`passage of the Food and Drug Administration Amendments Act (FDAAA) of 2007.
`12 Choudhry Y. REMS Interim Comment Set #1. Signed August 1, 2011 by Choudhry Y and Worthy K.
`
`
`
`Reference ID: 3078677
`
`8
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`

`

`3.6.4 Same Active Ingredient, Different Indication and Different Risk
`Management Approaches
`
`The agency evaluates an active ingredient based on the risk benefit profile for the
`intended population. To date, the Agency has not required a REMS for a product based
`only on the fact that the active ingredient already has a REMS for one population. For
`example, denosumab was originally approved under two tradenames for different
`indications. Prolia was initially approved for the treatment for post-menopausal
`osteoporosis (PMO). At that time, a REMS for Prolia was required and approved
`consisting of a Medication Guide and communication plan to “inform healthcare
`providers about the risks of serious infections, dermatologic adverse reactions, and
`suppression of bone turnover, including osteonecrosis of the jaw.” Under the tradename
`Xgeva, denosumab was approved for prevention of skeletal-related events in patients
`with bone metastases from solid tumors. A REMS was not required given the resulting
`differences in the risk benefit profile when considering the patient populations (post-
`menopausal women vs cancer patients with bone metastases) and prescribing populations
`(internists vs oncologists).
`
`3.7 PRODUCTS AFFECTED
`Mifeprex (and pending generics) are potentially affected because they are or will only be
`available under a restrictive REMS.
`
`4 RISK MANAGEMENT CONSIDERATIONS
`The following factors are important to consider:
` Burden to the intended population
`It is important to ensure that the intended treatment population can receive Korlym in
`a timely, dependable manner in the least burdensome way. Any restrictions will
`impede access with little to no benefit to Cushing’s syndrome population.
`
` Confidentiality/Privacy
`Confidentiality and patient privacy is a significant issue with Mifeprex. To what
`extent do stakeholders who make, distribute, dispense, prescribe, and use Korlym
`need protection from a confidentiality perspective?
`
`
`
` 
`
`
`
`The purpose of a REMS is to ensure the benefits of the drug outweigh its risks.
`Confidentiality and concern regarding the safety of the prescribers, pharmacists, and
`patients does not meet criteria. Confidentiality can be maintained without a REMS.
`Privacy may be better maintained if there are no systems in place to track formally
`prescribers and patients. Risk to pharmacies that stock the drug should be considered
`but it is outside the purview of a REMS.
`
` Reproductive potential for various possible Korlym off-label use populations
`
`9
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`Reference ID: 3078677
`
`

`

`As stated in section 3.4.1.2. above, there are a variety of uses for mifepristone
`. The therapeutic areas included below are more likely to
`include females of reproductive potential than other uses
`). A formal
`epidemiologic review was not conducted to estimate of the proportion of females of
`reproductive potential for each use. However, the following observations and/or
`assumptions were made:
`
`
`
`The degree to which Korlym will be used off label for the above uses is unknown.
`
`
` Extent of current off-label use
`Current Mifeprex drug utilization information is not informative in predicting broader
`uses for Korlym. In the September 19, 2011 mifepristone drug use review using
`commercial databases was conducted, off-label use was described as “uncommon”
`based on information obtained through a sample of medical offices and outpatient
`clinics. Sales distribution data was not available. The lack of findings are not
`surprising given the design of the Mifeprex REMS.
`
`5 RISK MANAGEMENT OPTIONS
`DRISK analyzed more than six risk management options to address intended termination
`of pregnancy by:
` HCPs outside of Mifeprex REMS
` women who seek to terminate a pregnancy and are not under the care of an HCP
`Ultimately, three options were considered.
`
`1. No REMS and voluntary restricted distribution through specialty
`pharmacies/distributors
`
`This REMS option may minimize diversion and subsequent misuse by
`minimizing the number of pharmacies stocking and dispensing Korlym for
`outpatient use. This option is in alignment with DMEP and DRISK’s assessment
`that a REMS is not necessary to assure the safe use of mifepristone for treating
`patients with Cushing’s syndrome because we believe the likelihood that a
`Cushing’s patient experiences “serious complications” relating to pregnancy
`termination are low.
`
`
`
`Reference ID: 3078677
`
`10
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`

`

`This approach is also consistent with misoprostol and methotrexate, both of which
`are known abortifacents and do not have a REMS to address that risk. This
`approach is used to prevent misuse of the growth hormone products.
`
`
`2. REMS with ETASU – dispensing through certified specialty pharmacies
`
`
`This REMS option may minimize diversion and subsequent misuse by
`minimizing the number of pharmacies stocking and dispensing Korlym for
`outpatient use. In addition, Corcept would be required to provide FDA an
`assessment of how the REMS is achieving its goals.
`
`This option does not address intended termination of pregnancy with Korlym.
`
`
`3. REMS with ETASU – prescriber certification (agreement not to use for
`termination of pregnancy) and distribution through certified specialty pharmacies
`that are willing to track inventory
`This REMS option would minimize diversion and subsequent misuse as
`described above. In addition, certified pharmacies (for outpatient dispensing, not
`inpatient hospital pharmacies) would verify that prescribers were certified.
`Prescriber certification would consist of agreement not use Korlym for pregnancy
`termination. The addition of prescriber certification would address the risk of
`intended termination of pregnancy with Korlym.
`
`
`These options assume that the safety labeling is maximized to address Korlym use in
`pregnancy.
`
`6 DISCUSSION
`The issue of how to address intended termination of pregnancy was discussed at the
`REMS Oversight Committee meeting on September 29, 2011 and at a Center Director
`Briefing on November 3, 2011.
`DMEP and DRISK presented at both meetings that women with Cushing’s syndrome are
`unlikely to be or become pregnant given the effects of their disease on the reproductive
`system and the effects of daily mifepristone treatment. Therefore, addressing the risk of
`fetal loss associated with Korlym was not discussed because 1) pregnancy is not a likely
`event in the intended population and; 2) the use of Korlym for “off-label” uses (in women
`more likely to be pregnant) is unknown and available data do not indicate that
`mifepristone would be first line treatment for any diseases or conditions at this time. For
`these reasons, there was general agreement that fetal loss can be adequately addressed
`through labeling and is not necessary to require additional safe use measures through a
`REMS at this time.
`The team stated that for any risk management approach, it is important to ensure that the
`intended treatment population can receive Korlym in a timely, dependable manner in the
`least burdensome way. Any restrictions could impede access without benefit to the
`intended population.
`
`
`
`
`Reference ID: 3078677
`
`11
`
`

`

`The primary focus shifted to whether or not a REMS is necessary for Korlym to maintain
`the integrity of the Mifeprex REMS. While the absence of any restrictions on Korlym
`could undermine the safe use conditions required by the Mifeprex REMS, a number of
`other factors are important considerations including:
` The burden (reduced access, treatment delays) of a restrictive REMS to the Cushing’s
`population without any benefit from the REMS for this population.
` Overall drug exposure and subsequent access is anticipated to be small given the
`small size of the intended use population and lack of a signal for substantially broader
`use.
` The sponsor’s plan to distribute Korlym through a specialty pharmacy regardless of
`the REMS. If necessary, this provides the sponsor the ability to monitor use more
`closely.
` The cost - If the cost of this orphan product is substanial, it may be expensive to
`obtain and deter use for pregnancy termination as well as other off label uses. In
`addition, third party payors/reimbursement may play a substantial role in influencing
`prescribing behavior. It is unknown how much Korlym will cost and how cost will
`impact prescribing behavior.13
`The need for some monitoring of use was discussed. Commercial drug use databases will
`not provide FDA with adequate estimates of Korlym use because Korlym will be
`dispensed through a specialty pharmacy. As noted above, using a single specialty
`pharmacy does allow the sponsor the ability to monitor use more closely through its
`business contract with the specialty pharmacy. Similarly, commercial drug use databases
`are not able to provide an accurate estimate of Mifeprex use due to how it is distributed
`and dispensed. The first REMS assessment for Mifeprex is due June 2012 which we
`anticipate will provide a baseline to quantify current Mifeprex use. Given these
`considerations and the discussion with the Center Director, we agree that a post-
`marketing requirement (PMR) study to obtain Korlym use data (age, gender, dose,
`duration of treatment) “to better characterize the incidence rates of adverse events with
`Korlym” is prudent. Monitoring drug use data for both Mifeprex and Korlym, in
`conjunction with reports of serious adverse events resulting from pregnancy terminations
`outside of the Mifeprex REMS, will be important factors in future regulatory action to
`address any compromise to the Mifeprex REMS.
`
`7 CONCLUSION
`A REMS for Korlym is not necessary to ensure that the benefits of the drug outweigh its
`risks at this time. We agree that it is prudent to monitor use through a PMR. If data
`indicate that this approach compromises the integrity of the Mifeprex REMS and results
`in serious adverse events, or additional serious safety signals arise, further regulatory
`action must be considered.
`
`
`ATTACHMENTS
`
`
`13 Planned parenthood charges $300-800 for a medical abortion (includes diagnostic testing, mifepristone, and
`misoprostol).
`
`
`
`Reference ID: 3078677
`
`12
`
`

`

`ATTACHMENT 1: Drugs with a risk associated with an off-label use
`
`
`Indication
`
`Off-label use*
`
`Contraindication
`
`Boxed Warning
`
`Drug
`
`Misoprostol
`(Cytotec)
`
`Abortifacient
`Efficacy
`When used alone –
`variable (~40-60%);
`used in combination
`with MTX or MFP
`efficacy is higher
`
`(Source - Micromedex)
`
`NSAID-induced
`gastric ulcers
`
`“Cytotec should not be
`taken by pregnant
`women to reduce the risk
`of ulcers induced by
`NSAIDs ”
`
` Postpartum
`hemorrhage
` Cervical ripening,
`labor induction
` Pregnancy
`termination
`
`“Cytotec administration to
`women who are pregnant
`can cause abortion …
`Cytotec should not be taken
`by pregnant women to
`reduce the risk of ulcers
`induced by NSAIDs…
`Patients must be advised of
`the abortifacient property
`and warned not to give the
`drug to others … ”
`
`Methotrexate
`(MTX)
`
`When used alone – (IM
`injxn – variable); in
`combination with
`misoprostol efficacy is
`higher (80-90%; small
`Ns)
`
`(Source - Micromedex)
`
`
`
`
`
`Cancer
`Psoriasis
`Rheumatoid
`arthritis
`including
`juvenile
`
` Other
`Autoimmune
`diseases
` More cancer
` Pregnancy
`termination
`
`“MTX has been reported to
`cause fetal death and/or
`congenital anomalies
`Therefore, it is not
`recommended for women
`of childbearing potential
`unless there is clear medical
`evidence that the benefits
`can be expected to
`outweigh the considered
`risks Pregnant women with
`psoriasis or rheumatoid
`arthritis should not receive
`MTX ”
`
`
`
`“MTX can cause fetal
`death or teratogenic
`effects when
`administered to a
`pregnant woman MTX
`is contraindicated in
`pregnant women with
`psoriasis or rheumatoid
`arthritis and should be
`used in the treatment of
`neoplastic diseases only
`when the potential
`benefit outweighs the
`risk to the fetus Women
`of childbearing potential
`should not be started on
`MTX until pregnancy is
`excluded and should be
`fully counseled on the
`serious risk to the fetus
`should they become
`pregnant while
`undergoing treatment ”
`*The off-label uses are general and based on tertiary sources; not on a formal drug use analysis.
`
`
`
`
`
`
`Reference ID: 3078677
`
`13
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SUZANNE C BERKMAN ROBOTTOM
`01/27/2012
`
`CLAUDIA B KARWOSKI
`01/27/2012
`concur
`
`Reference ID: 3078