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FDA-approved Makena[R] and pharmacy-compounded 17P--understanding the differences that may exist pharmacologically and clinically.

After publication of the results of the Meis Trial (1) in 2003 demonstrating the benefits of weekly administration of intramuscular 17P (17-alpha hydroxyprogesterone caproate, or hydroxyprogesterone caproate, or OHPC, referred to as 17P for brevity) when administered between 16 and 36 6/7 weeks of reducing the risk of recurrent preterm birth (PTB), the only available form of the medication for this indication was from compounding pharmacies.

Pharmacy compounding involves the preparation of a prescribed customized medication that would not otherwise be available for an individual patient. For example, a patient may need a medication to be produced without a dye or preservative due to allergies, or a medication may need to be made in a liquid or suppository form for a patient who cannot swallow a pill, or a dose is needed that is not otherwise available, or, as in the case of 17P, it was not commercially available at that time.

Compounded medications are not FDA-approved, and the FDA advises that it "does not verify the safety or effectiveness of compounded drugs..... Compounded drugs also lack an FDA finding of manufacturing quality." (2)

There are inherent risks associated with the use of compounded medications, particularly those that are injected rather than topical, due to the less stringent FDA oversight for compounded products. (2) However, for several years the compounded formulation of 17P was all that was available for this indication, and as a result some physicians who were not comfortable with the compounded option were not offering the therapy to appropriate patients.

In February 2011, the FDA-approved formulation of 17P (Makena[R], hydroxyprogesterone caproate injection (AMAG Pharmaceuticals), available for the prevention of PTB in women with singleton pregnancies who had previously delivered preterm. This meant that physicians and patients could finally be confident that the product they were receiving met the highest standards for pharmaceutical manufacturing.

FDA-approved medications are produced and tested in accordance with good manufacturing practices (GMPs), which are federal statutes that govern the development, production, testing and monitoring of pharmaceutical products for quality, safety, consistency, and efficacy. Compounded medications are not subject to GMPs, so quality, sterility, and safety may not be assured, and dosing may differ from one batch to the next, or one compounder to another.

Compounded products are not generic equivalents of branded medications. To gain FDA approval, generic drugs must also be produced in accordance with GMPs. TABLES 1 and 2 highlight the differences between FDA-approved medications and compounded medications: (3)

Because of some initial medication access issues after the launch of an FDA-approved hydroxyprogesterone caproate injection, while acknowledging a "greater assurance of safety" with the use of the FDA-approved product, for a brief period of time in 2011 the FDA announced "enforcement discretion" regarding its usual prohibition of prescribing compounded medications when an FDA-approved drug was available, stating it could revisit the issue at any time. (4)

In June 2012 the FDA did just that, and issued a new statement containing the following: "If there is an FDA-approved drug that is medically appropriate for a patient, the FDA-approved product should be prescribed and used. Makena[R] was approved based on an affirmative showing of safety and efficacy. The company also demonstrated the ability to manufacture a quality product. The pre-market review process included a review of the company's manufacturing information, such as the source of the API (raw materials) used in the manufacturing of the drug, proposed manufacturing processes, and the firm's adherence to current good manufacturing practice. Compounded drugs do not undergo the same premarket review and thus lack an FDA finding of safety and efficacy.... Therefore, when an FDA-approved drug rather than a compounded drug is commercially available, the FDA recommends that practitioners prescribe the FDA-approved drug rather than a compounded drug unless the prescribing practitioner has determined that a compounded product is necessary for the particular patient and would provide a significant difference for the patient as compared to the FDA-approved commercially available drug product." (2)

Attention became more focused on patient risks from compounded medications later that year in October 2012, when there was an outbreak of fungal meningitis infections linked to contaminated steroid injections compounded at the New England Compounding Center (NECC). (5) This outbreak killed 64 patients and seriously sickened over 750. This brought about a massive recall of compounded drugs made at the NECC and distributed nationwide, including thousands of doses of compounded 17P. This and other serious outbreaks focused concerns on the risks of large-scale compounding (sometimes called "manufacturing under the guise of compounding"). A bipartisan Congress subsequently passed the Drug Quality and Security Act (DQSA), signed into law by President Obama in November 2013, putting significant restrictions on compounders, stating that pharmacies "may not compound any drug that is essentially a copy of an approved drug." (6) Despite this prohibition, compounding of 17P has continued in some locales.

In 2014 the FDA again stressed the importance of "using an FDA-approved drug product, such as Makena[R], instead of a compounded drug except when there is a specific medical need (eg, an allergy) that cannot be met by the approved drug. The FDA is not aware of any scientifically reliable evidence demonstrating that compounding 17P without a preservative or in an oil base different than the one used in Makena[R] produces a significant difference for an identifiable group of patients (aside from the rare patient who is known to be allergic to either the preservative or the oil base)." (7)

Some providers are under the misimpression that the 17P medication used in the original Meis trial was compounded. It was not. To clarify the issue, Dr. Meis published a letter in the American Journal of Obstetrics and Gynecology in 2012 noting that the supplies used in the original trial were made in GMP-compliant pharmaceutical facilities, that this formed the basis of the GMPs used to produce the FDA-approved hydroxyprogesterone carproate version, and that "it would be misleading" to state that the 17P came from compounding pharmacies. (8)

FDA-approved hydroxyprogesterone caproate injection is now available in a sterile preservative-free single dose vial, (9) so providers who had opted for compounded 17P to avoid the preservative (perhaps not a good idea due to infections sometimes linked to improper sterility conditions present in some compounding facilities, can now administer a preservative-free FDA-approved product.

Some insurers have pressured providers to use compounded 17P over the FDA-approved medication. The use of an unapproved compounded drug confers additional riskwith no commensurate benefit. Compounded 17P is not approved by the FDA. The FDA recommendations are unequivocal, and should be shared with insurers when preauthorization for the FDA-approved medication is requested. Fortunately because the use of FDA-approved hydroxyprogesterone caproate injection rather than compounded 17P has become the standard of care, insurance coverage for the FDA-approved product is generally available. The manufacturer also has a program of financial assistance to help make this important and effective therapy accessible for all appropriate patients.

Another version of hydroxyprogesterone caproate was originally sold starting in 1956 under the brand name Delalutin. That drug was withdrawn from the market in 2001 "for reasons unrelated to safety concerns." (10) The FDA recently approved production of a generic version of Delalutin. When available, it is anticipated that the indication for this generic will be the same as for Delalutin. That is, it will be FDA-approved for use in nonpregnant women "for the treatment of advanced adenocarcinoma of the uterine corpus (Stage III or IV); in the management of amenorrhea (primary and secondary) and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer; as a test for endogenous estrogen production ("Medical D&C"); and for the production of secretory endometrium and desquamation." (10,11) This generic version of hydroxyprogesterone caproate will only be available in a 5 mL vial containing a preservative, unlike the currently available product approved by the FDA for the PTB indication. Use of this generic in pregnant women for PTB reduction would be considered "off label," which may impact on insurance coverage.

The FDA encourages patients to clarify with their provider whether they are being given the FDA-approved hydroxyprogesterone caproate injection versus compounded 17P. It is incumbent on the provider to document a specific reason for use of the compounded medication or a version not FDA-approved for PTB reduction if the decision is made to not follow FDA guidelines.


(1.) Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-2385.

(2.) Updated FDA Statement on Compounded Versions of hydroxyprogesterone caporate (the active ingredient in Makena[R]). http:// Published June 15, 2012. Updated August 3, 2012. Accessed July 28, 2016.

(3.) Gudeman J, Jozwiakowski M, Chollet J, Randell M. Potential risks of pharmacy compounding. Drugs R D. 2013;13(1):1-8.

(4.) FDA Statement on Makena[R] ucm249025.htm. Published March 30, 2011. Updated November 8, 2011. Accessed July 28, 2016.

(5.) Eisler P, Schnaars C. Safety, sanitary problems prompt scores of drug recalls. USA Today, compounding-pharmacy-recalls-inspectionscontamination/16472741/. Published October 7,2014. Accessed July 28, 2016.

(6.) Drug Quality and Security Act of 2013. hr3204/text. Published November 21, 2013. Accessed July 28, 2016.

(7.) FDA Statement on Hydroxyprogesterone. Drugs/GuidanceComplianceRegulatorylnformation/Pharmacy Compoundlng/ucm402614.htm. Published December 9, 2014. Accessed July 28,2016.

(8.) Meis PJ. The source of 17P used In NICFHD trial. Am J Obstet Gynecol. 2012;207(5):e11; author reply e12.

(9.) Makena[R] FDA Package Insert, drugsatfda_docs/label/2013/021945s005lbl.pdf. Published August 2013. Accessed July 28, 2016.

(10.) Federal Register: Determination That DELALUTIN (hydroxyprogesterone caproate) Injection, 125 Milligrams/Milliliter and 250 Milligrams/Milliliter, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness. Federal Register. ation-that-delalutin-hydroxyprogesterone-caproate-injection-125-milligramsmilliliter-and-250. Published June 25, 2010. Accessed July 28, 2016.

(11.) Flouse DW. FDA clears McGuff Pharma's generic Delalutin injection. Seeking Alpha News, Published October 5, 2015. Accessed July 28, 2016.

David L. Gandell, MD, has disclosed that he receives consulting fees and participates on the speakers' bureau for Duchesnay, AMAG Pharmaceuticals, Perrigo, and Shionogi.

David L. Gandell, MD

Clinical Professor of Obstetrics and Gynecology

Department of Obstetrics and Gynecology

Strong Memorial Hospital

University of Rochester School of Medicine and Dentistry

Rochester, NY
TABLE 1 FDA-approved drugs

* Includes branded and generic medications

* Manufactured in FDA-regulated and GMP-compliant
facilities; GMPs are federal statutes governing production
and testing of drugs

* Are tested for purity, consistency, and quality

* Must prove safety and efficacy

* Have standard product labeling and prescribing

* Must collect and report adverse events to the FDA

TABLE 2 Pharmacy compounded drugs

* Are exempt from GMPs; no singular formulation or
manufacturing process

* Are inconsistently tested to assess product quality

* Are not clinically evaluated for safety/efficacy

* Do not have standard product labeling or prescribing

* Are not required to report adverse events to FDA
(mandatory for FDA-regulated medications)

Abbreviation: GMP, good manufacturing practices.
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Author:Gandell, David L.
Publication:OBG Management
Date:Sep 1, 2016
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