Published in the January 2014 issue of the American Journal of Obstetrics & Gynecology is a study finding that 17-hydroxyprogesterone caproate (“17P”), an injectable medication that is used to prevent prematurity, obtained from 15 compounding pharmacies throughout the United States “did not raise safety concerns when assessed for potency, sterility, pyrogen status, or impurities.”

4. Published in the January 2014 issue of the American Journal of Obstetrics & Gynecology is a study finding that 17-hydroxyprogesterone caproate (“17P”), an injectable medication that is used to prevent prematurity, obtained from 15 compounding pharmacies throughout the United States “did not raise safety concerns when assessed for potency, sterility, pyrogen status, or impurities.”  (17P is an unusual, possibly unique, case, in that it is a medicine that is FDA-approved–sold under the brand-name Makena–but also available in compounded form.  For background, see here.)   In an editorial accompanying the AJOG study, Arnold Parry and Samuel Cohen write that “it is critical for obstetrical providers to understand that the cost of compounded 17P is much lower than that of the FDA-approved product, and many patients will have limited access to the FDA-approved product based on their insurance coverage.”

quoted from here

 

Ed Silverman's Blog--KV Pharma Loses Another Battle Over Makena

Ed Silverman states at his Pharmalot blog on 1/4/13:

KV Pharmaceutical may have emerged from bankruptcy in hopes of marketing still more of its controversial Makena treatment for reducing the risk of premature births. But the troubled little drugmaker, which has consistently locked horns with the FDA, last week lost another battle with the agency over its efforts to fend off competition to its controversial drug.

This time, the FDA rejected a petition KV had filed in hopes of preventing agency approval of a generic version of Delalutin, an older version of Makena, or hydroxyprogesterone caproate. KV argued that the FDA should not approve a generic because this would violate its exclusive marketing rights for Makena under the Orphan Drug Act (here is the petition).

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K-V Pharmaceutical Receives Court Approval of Hologic Settlement

Clears Path Forward for K-V's Pursuit of Chapter 11 Reorganization Plan

ST. LOUIS, Dec. 28, 2012 /PRNewswire/ -- K-V Pharmaceutical Company ("K-V" or "the Company") today announced that the U. S. Bankruptcy Court for the Southern District of New York, the Honorable Judge Allan L. Gropper presiding, approved the Company's settlement agreement with Hologic, Inc. ("Hologic Settlement"), and authorized the Company to enter into an $85 million debtor-in-possession ("DIP") financing to, among other things, fund the settlement.

"The resolution of the Hologic litigation is a major milestone in our restructuring. Now that it is resolved, K-V can focus on completing all other necessary steps for confirmation of a plan of reorganization and timely emergence from Chapter 11," said K-V President and CEO Greg Divis. "We are committed to our core women's health care business and continue to work closely with our customers to advance the care of the patients we serve."

Pharmacy-made pregnancy drug under scrutiny after meningitis outbreak

By Julie Appleby, Kaiser Health News

When a brand-name drug to help prevent premature births was approved last year, its $1,500-a-dose-price alarmed state and private sector insurance officials.

Many restricted use of the FDA-approved Makena in favor of $20- to $40-a-dose versions that had been made for years by pharmacies, saying that would give more women access to the treatment. Federal officials, sympathetic to such arguments, allowed the pharmacies to continue making the unapproved drugs.

But those decisions are now getting a second look following a deadly meningitis outbreak linked to a different pharmacy-made drug that has sickened hundreds of people and killed more than 25. No one has been reported injured by the pregnancy drug knockoffs. But the judgments made about Makena offer a window into the difficult tradeoffs between cost, safety and access sometimes confronted by policymakers and insurers at a time of growing angst over drug prices.

continue reading article here

The Makena Story

Michelle Oxman has written a blog entry entitled, What Does the Makena Story Tell Us About the Orphan Drug Act?, (September 24, 2012).  The article deals with why prescription drugs are a large portion of health care spending.  The article does a good job of explain the  Orphan Drug Act (ODA) (P.L. 97-414)  and of discussing the K-V v. FDA decision.  To read this article click here.

Article About Georgia to Cover Cost of Makena From Courthouse New Service

Georgia Ordered to Cover Costly Pregnancy Drug

By IULIA FILIP

ATLANTA (CN) - Georgia is violating Medicaid laws by failing to cover Makena, the only drug approved to treat preterm births, a federal judge ruled.
Makena is a progesterone-based drug designed to reduce the risk of premature birth in women pregnant with a single baby who have had a prior preterm birth. After the Food and Drug Administration approved the treatment in early 2011, KV Pharmaceutical charged $1,500 for Makena, while a compounded version was available for $20 a week. KV Pharma lowered the price to $690 in April 2011, but it continued to face protests from patient and doctor groups.
Though the Medicaid Act requires states to cover Makena for its FDA-approved indications, KV Pharma claimed that some states favored a compounded version of the drug over Makena and imposed unlawful restrictions on its product.
It filed federal complaints over the restrictions in Georgia and South Carolina.
In the Georgia case, the drugmaker insisted that Makena is theoretically a "covered outpatient drug." And yet, the Georgia Department of Community Health (DCH) restricted access to Makena by asking physicians to document the "medical necessity" of prescribing it over CHC, short for compounded hydroxyprogesterone caproate.
KV Pharma also sued the FDA in July for allowing compounding pharmacies to offer the lower-cost version of the drug, which contains the same active ingredients, but does not undergo the approval process.
The Northern District of Georgia refused to stay KV Pharma's lawsuit against the state pending the outcome of its action against the FDA, noting that the resolution of that lawsuit is irrelevant to the Georgia case.
U.S. District Judge Charles Pannell ruled that KV Pharma is likely to prove that Georgia Medicaid is breaking the law by failing to cover Makena.
"Because the court finds that the FDA drug approval process means something, the defendants' current policy favoring CHC over Makena is the opposite of what it should be," Pannell wrote. "As a result of the upside-down policy, the FDA-approved drug is not covered."
KV Pharma proved that the loss of revenue from Makena sales had contributed to its financial difficulties, including its filing for bankruptcy earlier this month, the court found.
Though Georgia may pay more for Makena, it will not suffer irreparable damages, and patients will benefit from an FDA-approved drug, the ruling states.
Pannell granted a preliminary injunction to KV Pharma, finding that Makena's Medicaid coverage would not disserve public interest.
"The parties agree that it is in the public interest to prevent preterm births," the ruling states. "Requiring the defendants to take steps to do so by utilizing the only FDA-approved drug as opposed to non-approved CHC, even at a higher cost, advances this public interest."

 

Article is found here.

K-V sues FDA over Makena in fight for survival

Thu Jul 5, 2012 6:59pm EDT

* Focus on cheaper versions of preterm birth drug Makena * K-V says FDA favored cost over science, safety
* Says will go bankrupt in 3-6 months without FDA action
* FDA has said compounded versions pose no risk
By Anna Yukhananov
WASHINGTON, July 5 (Reuters) - K-V Pharmaceutical Co is suing the U.S. Food and Drug Administration for not cracking down on compounded versions of its premature birth drug Makena, in a last-ditch fight for the company's survival.
Makena is an injectable hormonal medicine that reduces the risk of pre-term birth in women who have already delivered early in the past. K-V got approval to sell Makena last year, giving it a new lease on life after it was barred from making and marketing its own drugs due to repeated manufacturing problems.
But pharmacies had already been compounding a similar, and far cheaper, drug for years for people who had a prescription from a doctor. They use the active ingredient hydroxyprogesterone that has been available on the market without formal FDA clearance.
In its lawsuit, K-V said the FDA was addressing the financial concerns of insurance companies that cover the cost of medications instead of the needs of patients in declining to stop pharmacies from making cheaper versions of the Makena drug. By law, the FDA is only allowed to make decisions based on science, not cost.
K-V said Makena's sales are not enough for the company to satisfy its creditors, and it would go bankrupt within three to six months if the FDA failed to act, according to the lawsuit filed on Thursday in the U.S. District Court for the District of Columbia.
FDA spokeswoman Sarah Clark-Lynn said the agency does not comment on pending litigation.
Shares of K-V closed up 2.2 percent at 65 cents on the New York Stock Exchange, above the 45 cents it hit last week, but still a fraction of its value of over $3 a year ago.

FDA DILEMMA
The FDA normally issues warning letters to distributors of unapproved drugs, or may seize their products.
The FDA recently launched a drive to remove all unapproved drugs from the market due to safety issues, and encouraged companies to apply for formal clearance, but has not taken a hard line against the pre-term birth medications.
Patients and insurers preferred the pharmacy compounds, which cost $10 to $20 per injection versus the $1,500 K-V initially sought to charge for Makena after it was approved in February 2011.
K-V reportedly tried to stop pharmacies from compounding the drug by sending them letters saying they were violating the law and threatening to sue them.
But the FDA said it would take no action against pharmacies that offered the cheaper product, following complaints from U.S. lawmakers and health insurers that K-V was price-gouging for a drug already available on the market. K-V then slashed the price of Makena by 55 percent to $690.
K-V still argued that the older pharmacy compounds were not as safe or effective as Makena, as pharmacies don't need to meet the same manufacturing, safety and efficacy guidelines.
The FDA agreed in November to look into the issue, inspecting 16 samples of the compounded drug and of its active ingredient. In an announcement last month, the health regulator said these versions of Makena posed no major safety risks, though they contained some impurities.
"Although the analysis of this limited sample ... did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products," it said at the time.
The agency also said it was applying its "normal enforcement policies" in declining to stop the compounding pharmacies from making Makena, as it focuses its actions on products that are fraudulent or likely to cause harm.
The case is K-V Pharmaceutical Company v. FDA, U.S. District Court, District of Columbia, No. 12-01105.
New Article can be found here.

FDA Issues More Guidance About Makena®

In the form of Questions and Answers issued on June 29, 2012, the FDA recommends healthcare providers prescribe FDA-approved Makena (hydroxyprogesterone caproate injection) made by K-V  Pharmaceutical Company as the first-line for clinically-indicated patients. The FDA has not determined any other form of progesterone to be effective for this medical condition. The FDA also explained its enforcement policy towards compounded formulations of hydroxyprogesterone caproate. The FDA Questions and Answers state:

The FDA Questions and Answers are as follows: 

What is pharmacy compounding?

The FDA regards pharmacy compounding as the combining or altering of the ingredients of a drug by a licensed pharmacist to produce a drug tailored to an individual patient’s particular medical needs, based on a valid prescription from a licensed medical practitioner. For example, compounding may occur if a patient needs a medication to be produced without a dye or preservative due to an allergy, or needs a medication in a liquid or suppository form because the patient cannot swallow a pill.

Should health care professionals prescribe and patients take the FDA-approved drug product rather than the compounded product?

If there is an FDA-approved drug that is medically appropriate for a patient, the FDA-approved product should be prescribed and used. Makena 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 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 and lack an FDA finding of manufacturing quality. Therefore, when an FDA-approved 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.

How will a patient know if she is receiving Makena or a compounded product?

A patient can ask her health care provider what product is being administered. A label will also be visible on the vial or syringe with information such as the patient name, prescription number, and name of the product. Typically, if the pharmacy dispenses the FDA-approved product, it will have the brand name “Makena” on the label.

Will the agency take any enforcement action against pharmacies compounding versions of hydroxyprogesterone caproate products?

The FDA may take enforcement action against compounding pharmacies if warranted. The FDA makes its enforcement decisions about compounded products on a case-by-case basis after considering the particular facts at issue. As we explained in the June 15, 2012, statement¹, the compounding of any drug, including hydroxyprogesterone caproate, should not exceed the scope of traditional pharmacy compounding.

Are pharmacies free to compound large volumes of hydroxyprogesterone caproate as long as none of their drugs are tested and found to be unsafe?

No. The FDA does not consider compounding large volumes of copies, or what are essentially copies, of any approved commercially-available drug to fall within the scope of traditional pharmacy practice. One factor that the agency considers in determining whether a drug may be compounded is whether 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.
The FDA may take enforcement action against pharmacies that compound large volumes of drugs that are essentially copies of commercially available products and for which there does not appear to be a medical need for individual patients to whom the drug is dispensed.

The FDA stated it is using a risk-based approach to enforcement action against compounding pharmacies. The FDA also stated that its investigation did not identify a major safety issue, so does that mean that the FDA does not intend to take enforcement action against the compounders of hydroxyprogesterone caproate?

No. A risk-based approach to enforcement relates to how the FDA generally prioritizes its enforcement efforts. The FDA’s June 15, 2012 statement should not be interpreted to mean that the FDA will take enforcement action only if the agency identifies a particular safety problem. We reiterate that the compounding of any drug, including hydroxyprogesterone caproate, should not exceed the scope of traditional pharmacy compounding.

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1. /NewsEvents/Newsroom/PressAnnouncements/ucm308546.htm

Page Last Updated: 06/29/2012 

IACP Responds to FDA's Makena(R) 17-P Update

IACP has responded to the FDA's Makena(R) 17-P update issued last week by stating FDA Study Affirms no Major Safety Issues with Compounded 17-P. To read an article about IACP statement click here.  To read additional articles click here, here and here.

Updated FDA Statement on Compounded Versions of hydroxyprogesterone caproate (the active ingredient in Makena)

For Immediate Release: June 15, 2012
Media Inquiries: Erica Jefferson, 301-796-4988, Erica.Jefferson@fda.hhs.gov

Updated FDA Statement on Compounded Versions of hydroxyprogesterone caproate (the active ingredient in Makena)

FDA (or the Agency) approved Makena (hydroxyprogesterone caproate) in February 2011 for the reduction of the risk of certain preterm births in women who have had at least one prior preterm birth. Beginning many years before Makena was approved, a version of the active ingredient of Makena has been available to patients whose physicians requested the drug from a pharmacist who compounded the drug.

As explained in a November 8, 2011 statement, in October 2011, FDA received information from Makena’s sponsor, K-V Pharmaceuticals, regarding the potency and purity of samples of bulk hydroxyprogesterone caproate active pharmaceutical ingredients (APIs) and compounded hydroxyprogesterone caproate products. The Agency explained that FDA had carefully reviewed the data K-V submitted and would conduct an on-site review of the laboratory analyses. The Agency also stated that FDA had begun its own sampling and analysis of compounded hydroxyprogesterone caproate products and the bulk APIs used to make them.

FDA has completed its review, and the Agency is now providing a brief summary of the results. FDA collected samples of compounded hydroxyprogesterone caproate products and hydroxyprogesterone caproate APIs. These samples generally were collected from compounding pharmacies, doctor’s offices, API distributors, and APIs offered for importation.

• FDA tested 16 samples of hydroxyprogesterone caproate API using the methods specified in the United States Pharmacopeia (USP) as well as the methods used in the Makena new drug application (NDA). 
  • All 16 API samples passed USP tests for potency (97-103 percent) and purity and all 16 API samples passed the potency tests in the Makena NDA.
  • All 16 of the API samples passed the total purity standard in the Makena NDA but failed the Makena NDA’s limit for unidentified impurities.
  • FDA also isolated and identified four impurities that appeared at levels above those permitted in the Makena NDA. Based on information available to FDA, the impurities observed in these samples do not raise safety concerns.  
• FDA also tested 13 samples of compounded hydroxyprogesterone caproate prepared by eight pharmacies.
  • One of 13 samples was subpotent and was in the range of 80 percent of declared potency. (The standard for potency is 90-110 percent). All 13 of the samples met the standard in the Makena NDA for total purity.
  • Two of the 13 samples failed to meet the standard for unidentified impurities in the Makena NDA.

FDA also obtained the available retained samples of compounded products from the laboratories that K-V hired to perform the tests on the compounded products that were submitted to the agency in October 2011. FDA’s testing of the retained samples found that three of 26 samples failed the standard for potency (90-110 percent) using the method in the Makena NDA. (The samples were not large enough for FDA also to test them using the USP method.)  The three products that failed potency testing were in the 115 percent range. Seven of 26 samples failed the standard for unidentified impurities in the Makena NDA.

Although the analysis of this limited sample of compounded hydroxyprogesterone caproate products and APIs did not identify any major safety problems, approved drug products, such as Makena, provide a greater assurance of safety and effectiveness than do compounded products. Before approving the Makena NDA, FDA reviewed manufacturing information, such as the source of the API used by its manufacturer, proposed manufacturing processes, and the firm’s adherence to current good manufacturing practice.

The drugs that pharmacists compound (including compounded hydroxyprogesterone caproate) are not FDA approved, which means they do not undergo premarket review nor do they have an FDA finding of safety and efficacy. Compounding large volumes of drugs that are copies of FDA-approved drugs circumvents important public health requirements, including the Federal Food, Drug, and Cosmetic Act’s drug approval provisions. Consumers and health professionals rely on the Act’s evidence-based drug approval process to ensure that drugs are safe and effective. For that reason, one factor that the agency considers in determining whether a drug may be compounded is whether 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.  

FDA emphasizes that it is applying its normal enforcement policies for compounded drugs to compounded hydroxyprogesterone caproate. The compounding of any drug, including hydroxyprogesterone caproate, should not exceed the scope of traditional pharmacy compounding. As the Agency has previously explained, FDA generally prioritizes enforcement actions related to compounded drugs using a risk-based approach, giving the highest enforcement priority to pharmacies that compound products that are causing harm or that amount to health fraud.

Independent Laboratory Testing Demonstrates Important Quality Differences Between FDA-Approved Makena® and Compounded 17P Formulations

 

 

FDA Issues Statement on Makena® on November 8, 2011

ST. LOUIS, Nov. 8, 2011 /PRNewswire/ -- Recent testing conducted by independent laboratories, commissioned by Ther-Rx Corporation, a subsidiary of K-V Pharmaceutical Company (the "Company") (NYSE: KV.A/KV.B), shows that multiple samples of both compounded 17P drug formulations and active pharmaceutical ingredient (API) that may be used in compounded 17P failed to meet certain established standards for potency and purity. These findings, which have been submitted to the U.S. Food and Drug Administration (FDA), demonstrate important quality differences in these compounded 17P formulations when compared to FDA-approved Makena® (hydroxyprogesterone caproate injection).

"We commissioned this research because moms and healthcare providers deserve to know whether medications prescribed during pregnancy meet FDA's quality standards," said Greg Divis, President and CEO of K-V Pharmaceutical Company. "This research demonstrates important differences in product quality between FDA-approved Makena® and these compounded 17P formulations. Healthcare providers and patients have no practical way of ensuring that compounded 17P formulations meet FDA's quality standards. Now that FDA-approved Makena® is available, America's high-risk moms deserve a product that consistently meets FDA's standards."

On Nov. 8, 2011, the FDA issued a statement on Makena® acknowledging it has received information from the Company regarding the potency and purity of samples of bulk hydroxyprogesterone caproate APIs and compounded hydroxyprogesterone caproate products. FDA stated, "According to the analysis of this information provided by K-V, there is variability in the purity and potency of both the bulk APIs and compounded hydroxyprogesterone caproate products that were tested." The agency has begun its own sampling and analysis of compounded hydroxyprogesterone products and the bulk APIs used to make them. In FDA's statement, the agency "reminds healthcare providers and patients that before approving the Makena® new drug application, FDA reviewed manufacturing information, such as the source of the API used by the manufacturer, proposed manufacturing processes and the firm's adherence to current good manufacturing practice. Therefore, as with other approved drugs, greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product."  

The full text of the FDA statement is available athttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279098.htm

Overview of Research

The active pharmaceutical ingredient in FDA-approved Makena®, hydroxyprogesterone caproate, is sourced exclusively from the same FDA-registered and FDA-inspected manufacturer that supplied the API used in the NICHD study that served as part of the basis for FDA approval of Makena®. To the Company's knowledge, this is the only manufacturer of hydroxyprogesterone caproate known to have an active Drug Master File with the FDA.  

Research commissioned by Ther-Rx shows that the API used in compounded 17P formulations originates primarily from facilities in China that are neither registered with nor inspected by the FDA. This research also found that the vast majority of entities claiming to be original manufacturers of hydroxyprogesterone caproate are actually re-packagers, re-sellers, brokers or distributors of hydroxyprogesterone caproate that is actually manufactured in China.

The Company also commissioned independent laboratory testing to assess samples of API and compounded 17P formulations and, as such, does not purport to assess the quality of all of the various compounded 17P formulations and hydroxyprogesterone caproate API available on the market. Specifically, the laboratory testing included:

• 10 samples of API used in compounded 17P formulations provided by 10 different suppliers of API. Seven of the suppliers were determined to be original manufacturers of API that are located in China and that, to the Company's knowledge, do not appear to have been registered with or inspected by the FDA. The other three were identified as U.S.-based resellers of API, whose product is also believed to originate from China.
• 30 vials of compounded 17P formulations, prepared by 30 different compounding pharmacies across 15 states.

The independent laboratories measured the quality of each API sample and compounded 17P vial against certain quality standards required by FDA for Makena®. The samples also were evaluated by these labs against certain U.S. Pharmacopeia (USP) standards for hydroxyprogesterone caproate and hydroxyprogesterone caproate injection, because some compounding pharmacies claim that their compounded formulations meet USP criteria. The laboratories analyzed the API and compounded 17P drug formulations to assess potency, chemical impurities and drug identity.

Key Laboratory Testing Findings

Active Pharmaceutical Ingredient (API)

• One API sample sent from a Chinese manufacturing facility was not the correct active pharmaceutical ingredient. Although the package was sent to the United States labeled in Chinese as hydroxyprogesterone caproate (HPC), the active ingredient failed the drug identity test for HPC. Further laboratory analysis conclusively proved that the substance was glucose instead of HPC.
• 80 percent (8 of 10) of the API samples failed to meet at least one FDA standard for unknown impurities.
• 50 percent (5 of 10) of the API samples failed to meet the USP standard for potency.
• The paperwork (certificates of analysis) that arrived with API shipped from China was often missing or incomplete. Such gaps in paperwork can make it difficult to track back specific product to specific manufacturing facilities, which is critically important should a problem with the medication arise.

Compounded 17P Formulations

• 27 percent (8 of 30) of the compounded 17P vials tested failed to meet the USP standard for potency. The potency values of the compounded 17P vials ranged from just over half to a level more than 2.5 times the labeled potency. If these vials were administered to patients, some patients would not have received the dose of 17P that was reviewed and subsequently approved by FDA for safety and efficacy in this patient population. This variability in potency was comparable to those found in FDA's limited survey of compounded drug products conducted in 2006, which is available at:  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm204237.htm
• 53 percent (16 of 30) of the vials of compounded 17P had levels of unknown impurities that exceeded at least one standard required by the FDA for Makena®. The potential toxic effects of these unidentified compounds in the intended patient population are unknown.  
• Taken together, two-thirds (20 of 30) of the compounded 17P vials failed to meet at least one USP requirement (a standard used by some compounding pharmacies) or at least one FDA quality standard required of Makena® for potency and/or purity levels. Information was not obtained regarding the sterility of, or potential presence of endotoxins in, the compounded 17P vials.  
• FDA-approved Makena® must meet FDA's quality standards before release for patient use.

Article is found here
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K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China

K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China

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