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On October 14, 2011, ABC Nightline’s Chris Cuomo aired an investigation of Drospirenone (DRSP) brith control pills such as Yaz / Yasmin. 

The same story played on Good Morning America on October 15, 2011.  The story discusses the tragic case of Ms. Ubersox, a 24 year old who as a result of watching TV commercials for Yaz aired by Bayer, decided to try Yaz in order to lose weight in preparation for her upcoming marriage. 

After taking Yaz she tragically suffered bilateral pulmonary emboli, and her heart stopped on the way to the hospital.  She could not breath due to the bilateral pulmonary emboli. 

She went into coma and woke up blind. 

She lost her work, her fiancé, and most tragically of all, she lost her sight. 

Bayer would not talk in any substantial manner to the ABC reporters and avoided their calls as shown on the Nightline story on ABC (available on YouTube). 


Also in recent news, on September 26, 2011, the FDA revealed that it is organizing an advisory panel in December 2011 to evaluate and discuss the data and science about “VTEs”, also known as blood clots, connected with the use of DRSP or drospirenone in birth control pills.  The FDA has concern about these risks.

Some estimates have around one hundred deaths attributed to Yaz and Yasmin oral contraceptives as of the time of the writing of this article. 

In 2003 and 2008 the FDA released severe warnings about advertising claims made by Bayer, the manufacturer of Yaz and Yasmin.  If you or a loved one have suffered injury after taking Yaz, Yasmin, or Ocella, we would like to speak with you and potentially include you in our collection of claims we are preparing to file against the manufacturers of these products.

The Mulligan Law Firm has experience representing plaintiffs in oral contraceptive and other types of contraceptive litigation. 

We have a free information packet related to Yaz, Yasmin, and Ocella that we would like to mail you if you fill out any of the contact forms on this website or call us at 888 446 8087.

The oral contraceptives Yaz, Yasmin, and the generic form known as Ocella have all been linked to very serious circulatory issues such as blood clots, and gallbladder injuries. 

It is thought that a key component in these drugs raises potassium levels in the blood to dangerous levels causing many potential injuries such as:

  • Stroke
  • Blood Clots including Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT)
  • Heart Attacks / MI / Myocardial Infarction
  • Liver Tumors and Liver Issues
  • Death
  • TIA / Strokes
  • Kidney or Renal Disease
  • Pancreatitis
  • Gallbladder Disease
  • Thrombosis

Women who take these drugs may be at higher risk for injury if they have high blood potassium, kidney or liver issues / impairment, high blood pressure, adrenal gland issues / abnormalities, and / or women who are obese and / or diabetic.

Blood clots are particularly a concern.  Symptoms of blood clots may include, but are not limited to:

  • Pain in the legs, particularly in the back of the lower part of the leg.
  • Coughing up blood
  • Eye problems such as blindness, loss of vision, or blurring / blurred or double vision
  • Unusual swelling in the extremities / pain in the extremities
  • Sudden onset of severe headaches
  • Crushing, sharp, or pressured chest pain.
Drospirenone is the component in Yasmin, Yaz, and Ocella that is of concern.  These drugs are the first and only birth control medications on the U.S. market that use the 4th generation formulation of synthetic progesterone, drospirenone.  This is combined with a estrogen called ethinylestradiol.

These two components together has a diuretic effect that raises the blood potassium levels in those who take these medications and it is thought this is how blood clots, gallbladder damage, and other injuries result from these drugs.  Left without medical care, these injuries can be extremely serious and even result in death.


The FDA approved Yasmin in 2001 for birth control and the treatment of Premenstrual Dysphoric Disorder, (PMDD).  Later Yaz was approved by the FDA for the treatment of severe acne.

Yasmin, Yaz, and Ocella have been connected with increased risks of blood clots, heart attacks, and strokes.  This is not a new development, as other birth control medications such as the Ortho Evra patch also had side effects that are similar.

Yaz is also associated with serious gallbladder disease, and often the only way to treat the problem is gallbladder removal surgery.

The FDA warned Bayer, the company that manufactures Yaz and Yasmin, in both 2003 and 2008 for exaggerating the benefits and minimizing the risks of these oral contraceptive drugs.  The drugs increasingly showed evidence of issues that were of concern to the FDA, and the FDA took particular actions and concern regarding Bayer’s advertising of the drugs.

The FDA required Bayer to spend $20,000,000 on an advertising campaign to correct the misleading advertising.


The FDA has warned the manufacturers of Yasmin on four occasions regarding Yasmin.

LETTER NUMBER 1:  07/10/2003

On July 10, 2003, the FDA sent  a letter requiring the discontinuation of misleading Yasmin advertisements. 

The FDA warned Bayer that they are improperly implying superiority to other oral contraceptives. 

The letter states, “Specifically, the 60-second TV ad entitled “Goodbye Kiss” is misleading because it makes implied clinical superiority claims to other combination oral contraceptives and minimizes the important risk information that distinguishes Yasmin from other combination oral contraceptives.  As a result, the TV ad raises significant public health and safety concerns.” 

The letter further states, “Moreover, these claims are misleading because they imply superiority to other COCs (and thus do not offer the same product benefits as Yasmin Tablets) when such has not been demonstrated by substantial evidence or substantial clinical experience.  Finally, these claims are misleading because they misrepresent Yasmin’s mechanism of action by stating that Yasmin “uses a different kind of hormone.  One that may work with your body chemistry.”  However, COCs, including Yasmin, prevent ovulation by working against the usual body chemistry of a woman of childbearing potential by suppressing endogenous gonadotropins and, therby, inhibiting ovulation and altering other changes associated with the menstrual cycle.” 

The FDA warned Bayer that they minimized the health risks of Yasmin. 

The letter states, “Thus, by failing to add the necessary context to clarify that increased blood potassium is a safety risk rather than a clinical benefit, the ad misleadingly represents or suggests that Yasmin is safer than has been demonstrated by substantial evidence or substantial clinical experience.”   The letter continues, “In summary, the TV ad not only misleads consumers about the efficacy of Yasmin, the ad also minimizes important context about the health risks of the drug.”

The FDA ordered the Defendant manufacturers of Yasmin to discontinue the ads.

In conclusion, the letter states “Berlex should immediately discontinue the TV ad and all other promotional materials and activities for Yasmin that contain the same or similar violative presentations.” 

LETTER NUMBER 2:  10/03/08

On October 3, 2008 the FDA sent a second letter requiring Bayer to immediately cease dissemination of its “Not Gonna Take It” and “Balloons” advertisements.

The FDA warned that the advertisements known as “Not Gonna Take It” and “Balloons” are misleading.

FDA writes, “The TV Ads are misleading because they broaden the drug’s indication, overstate the efficacy of YAZ, and minimize serious risks associated with the use of the drug.” 

The FDA additionally writes, “The TV Ads misbrand the drug in violation of the Federal Food, Drug, and Cosmetic Act …”  And, “These violations are concerning from a public health perspective because they encourage use of YAZ in circumstances other than those in which the drug has been approved, over-promise the benefits and minimize the risks associated with YAZ.”

The letter also states that Bayer misuses selective PMDD Symptoms to Suggest PMS Relief from YAZ. 

FDA writes, “We note that the list of symptoms displayed in the TV Ads are accompanied by the text “YAZ treats PMDD” along with a SUPER reading “PMDD is a mood disorder related to the menstrual cycle.”  However, these disclosures do not suffice to communicate the material fact that YAZ is not approved for treatment of PMS or to overcome the implication created by the totality of the visuals and images in the ads that YAZ is appropriate for any woman who experiences the symptoms presented.  We also note that the voiceover states that “YAZ is the only birth control pill proven to treat the emotional and physical premenstrual symptoms that are severe enough to impact your life.”  However, this claim also fails to communicate that YAZ is not approved for treatment of PMS, and fails to distinguish between PMS and PMDD. 

Further, the letter states, “The totality of the visual and audio presentations in both TV ads suggest that YAZ is approved to treat women with any severity of the symptoms presented, including women with PMS, when this is not the case.  Thus, the TV Ads misleadingly broaden the indication of the drug.”

FDA states that the advertisements overstate alleged acne benefits of the drug.

FDA writes, “In addition, the TV Ads suggest that YAZ is approved for acne of all severities when this is not the case.”  ….  “These presentations fail to adequately convey that, as noted in the PI, “YAZ is indicated for the treatment of moderate acne vulgaris…”

FDA focuses on the distracting imagery and design of the advertisements. 

In one particularly interesting paragraph, FDA writes that the format and design of the advertisements minimize the risks, “The audio communication of serious risk disclosures during the “major statement” is minimized by distracting visuals, numerous scene changes, and other competing modalities such as the background music which combine to interfere with the presentation of the risk information.  In “not Gonna Take It”, the fast – paced visuals depict various women looking at pictures, trying on clothes, chatting at a café, stretching/exercising in a park, and walking down the street while the audio component describes the major risks associated with YAZ.  Similarly, in “Balloons,” the background music plays as fast-paced visuals depict various women running in a park, sitting on a scenic waterfront, smiling, walking out of a coffee shop, driving and singing, walking out on a balcony, using an elevator, walking through the street to join friends, in addition, to a pigeon on a building ledge and balloons being released and floating away.  These complex presentations distract from and make it difficult for viewers to process and comprehend the important risks being conveyed.  This is particularly troubling as some of the risks being conveyed are serious, even life-threatening.  The overall effect of the distracting visuals, graphics, concurrent supers and background music is to undermine the communication of important risk information, minimizing these risks and misleadingly suggesting that YAZ is safer than has been demonstrated by substantial evidence or substantial clinical experience.” 

In conclusion, FDA orders Bayer to immediately cease dissemination of the advertisements at issue.

“DDMAC asks Bayer to immediately cease dissemination of violative promotional materials for YAZ that are the same as or similar to those described above.  …. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials.  ….  If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion.” 

In short, FDA was very unhappy with Bayer.

LETTER NUMBER 3:  03/26/09

On 3/26/09 The FDA sent a third warning letter to Bayer finding that Bayer’s Yaz internet links violate the Federal Food, Drug, and Cosmetic Act and FDA implementing regulations.

FDA writes, “This letter notifies Bayer Healthcare Pharmaceuticals, Incorporated (Bayer), and, by copy, Shering Corporation (Shering), which markets Levitra on behalf of Bayer, that, as part of its monitoring and surveillance program, the Division of Drug Administration (FDA) has reviewed Bayer’s sponsored links on internet search engines (e.g., Google.com) for the following products:  LEVITRA® (vardenafil HCI) Tablets (Levitra), Yaz® (drospirenone and ethinyl estradiol) Tablets (YAZ), and Mirena ® (levonorgestrel-releasing intrauterine system) (Mirena).  The sponsored links cited in this letter are misleading because they make representations and/or suggestions about the efficacy of Levitra, YAZ, and Mirena, but fail to communicate any risk information associated with the use of these drugs.  In addition, the sponsored links for YAZ and Mirena inadequately communicate the drugs’ indications, and the sponsored links fail to use the required established name.  Thus, the sponsored links misbrand the drugs in violation of the Federal Food, Drug, and Cosmetic Act (the Act) and FDA implementing regulations.


FDA continues, in its letter to Bayer:


According to its FDA-approved PI, YAZ is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.

YAZ is also indicated for the treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women who choose to use an oral contraceptive as their method of contraception. The effectiveness of YAZ for PMDD when used for more than three menstrual cycles has not been evaluated.

YAZ has not been evaluated for the treatment of premenstrual syndrome (PMS).

YAZ is also indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy, and have achieved menarche. YAZ should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.

YAZ is associated with a number of risks, as reflected in the Boxed Warning, Contraindications, Warnings, Precautions, and Adverse Reactions sections of its PI.”


And, The FDA alleges overstatement of efficacy among other concerns:


“Inadequate Communication of Indication/Overstatement of Efficacy

The sponsored link for YAZ provides a very brief statement about what the drug is for; however, this statement is incomplete and misleading, suggesting that YAZ is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. Specifically, the sponsored link for YAZ misleadingly broadens the indication for YAZ by implying that all patients with moderate acne are candidates for YAZ therapy (“YAZ® Prevents Pregnancy, May Help Moderate Acne and PMDD”), when this is not the case. Rather, YAZ’s indication is limited to the treatment of moderate acne vulgaris in women at least 14 years of age who have achieved menarche, and it should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.”

FDA concludes:

“Conclusions and Requested Action

For the reasons discussed above, the sponsored links misbrand Levitra, YAZ, and Mirena in violation of the Act and FDA regulations. See 21 U.S.C. 352(a) & (n), 321(n); 21 CFR 201.10(g)(1), 202.1(b)(1), (e)(3)(i), (ii) & (e)(6)(i).

DDMAC requests that Bayer immediately cease the dissemination of violative promotional materials for Levitra, YAZ, and Mirena, such as those described above. Please submit a written response to this letter on or before April 9, 2009, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for these drugs as of the date of this letter, identifying which of these materials contain violations such as those described above, and explaining your plan for discontinuing use of such materials. Finally, we encourage you to review your promotional materials for the other prescription drug products that Bayer promotes in the United States and to discontinue or revise any materials with the same or similar violations, and request that your response address this issue as well.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD, facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS # 17307 in addition to the NDA numbers. We remind you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Levitra, YAZ, and Mirena comply with each applicable requirement of the Act and FDA implementing regulations.”

Once again, Bayer is requested to stop a form of advertising in a warning letter from FDA.


LETTER NUMBER 4:  08/05/09

On August 5, 2009, FDA wrote a fourth letter to Bayer warning that Bayer failed to properly test Yaz / Yasmin ingredients that were shipped to the United States Market.

FDA wrote:

“This letter is regarding a March 2-10, 2009 inspection of your active pharmaceutical ingredient (API) facility in Bergkamen, Germany, by U.S. Food and Drug Administration (FDA) Investigator Jose Cruz and Chemist Miguel Martinez. The inspection revealed significant deviations from U.S. current good manufacturing practices (CGMP) in the manufacture of non-sterile APls. These deviations were listed on an Inspectional

Observations FDA Form (FDA-483) issued to you at the close of the inspection.

These CGMP deviations cause your APls to be adulterated within the meaning of Section 501(a)(2)(B) [21 USC 351(a)(2)(B)] of the Federal Food, Drug, and Cosmetic Act (the Act). Section 501(a)(2)(B) states that drugs are adulterated when they are not manufactured,processed, packed, and held according to current good manufacturing practices. Failure to comply with CGMP constitutes a failure to comply with the requirements of the Act.



We have reviewed your April 7, 2009 written response to the FDA-483 observations. We acknowledge that some corrections appear to have been completed or will soon be implemented. However, your response does not adequately address some of the deficiencies. Specific violations found in the inspection include, but are not limited to:

1. Laboratory controls are deficient in that your firm has established procedures that allow for the averaging of out-of-specification (OOS) and within-specification analytical test results from separate samples. The use of these approved procedures resulted in API batches being released to the U.S. market based on passing averaged assay results.  [emphasis added]  Refer to FDA-483 Observation #2c and 2d. For example:



a. GMP Directive #CMSD08-50-01-1, Handling of Out-of-Specification Results


This procedure allows for the averaging of results into specification. It provides for the reportable, or averaged result, rather than the individual test results to be compared against the established specifications. The reported (average) result is defined as the final analytical result reported and compared against the specification. An individual value found outside the established specification is not defined as an DOS if, when averaged, the reportable result remains within specifications. An ODS result is defined as a reportable result (average) that is outside the defined acceptance criteria (e.g. specification).



b. LIMS (Laboratory Information Management System) procedure:



The inspection revealed that results for individual tests are calculated individually by the (b)(4) system and then averaged by your firm's Laboratory Integrated Management System (LIMS). The averaged result (not individual results) is then corrected for water content, if necessary. The release specification is applied only to the averaged result and not to the individual results. Refer to FDA-483 Observation #2d.



The investigators were informed during the inspection that the analyst is the first person to review the individual results. If the individual results do not vary more than (b)(4), the average of the results is permitted according to procedure #QCB.PKA00132, Determination of Values and Rounding of Results. This procedure allows the analyst to make the decision to re-inject the samples or to accept the assay result and continue documenting the values obtained as final results without conducting an investigation.



2. Your quality management system fails to ensure that APIs manufactured and released by your firm meet established specifications.  [emphasis added]  Refer to FDA-483 Observation #1.


Specifically, the API batches shown below were released based on reportable assay results obtained from the average of two independent sample results. One of the sample results was out-of-specification (ODS) while a second result was within specification. The averaged passing reportable assay result was compared against the established specifications, and the batches were released to the marketplace.


In your April 7, 2009 response you reported that you had conducted a retrospective investigation that extended to all "U.S. relevant" (i.e., sent to facilities that further processed them into finished drug products intended for the U.S. market) API batches produced between 2007 and 2009. You identified nine additional incidents where OOS results were averaged with passing results. In all cases, your firm concluded that no analytical errors had been identified and that the values were true DOS results. Your firm concluded that these OOS results were within the accepted variation of the analytical method and that the quality of these batches was not affected. We disagree with your rationale and conclusion. An assay test is used to determine potency, not method variability. The validation of your analytical method should address robustness or variability, while system suitability is designed to address instrument variation performance, which was met in each of these instances. We believe that these results were true ODS values and that these batches should not have been released for distribution.  [emphasis added]



In your written response, you indicate that your current procedure allows the average of two individual sample preparation results, if the difference of the single values does not exceed (b)(4) absolute. You state that this is appropriate averaging and in line with the FDA OOS guidance document. We disagree with your rationale and interpretation of the FDA OOS guidance. Your firm prepares two to three separate samples, which are assayed individually. We expect you to treat each of these results independently, and not to average an OOS result with a passing individual result. The hiding of an OOS result in the average is an unacceptable practice. Please refer to the October 2006 Guidance for Industry-Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Products, that states in part IV.C.1.b., "Reliance on averaging has the disadvantage of hiding variability among individual test results. For this reason, all individual test results should normally be reported as separate values. "Your revised DRAFT SOP QCB.PKA00132, "Determination of Values and Rounding of Test Values" appears adequate, in that going forward you will treat each individual test result independently and will only average values that are within-specification. Please submit a translated version of the revised SOP once it is approved, along with appropriate training documentation.



We remain concerned with your released and distributed API batches used in the manufacture of finished products intended for the U.S. market, in which the reportable results were based on the average of out-of-specification and within-specification analytical test results.  [emphasis added]  Include in your response to this letter a complete list of all API batches shipped to the U.S. (also include lot numbers, date of shipment, customer name and address), using reportable passing average results consisting of out-of-specification and passing results. Please inform this office of any additional corrective action you plan to take to correct this violation.



We are concerned that GMP Directive #CMSD08-50-01-1, Handling of Out of Specification Results, is a corporate directive that may be in place in other manufacturing and testing facilities. Provide in your response to this letter the corrective and preventive actions implemented throughout your corporation to address this deficiency, and ensure that adulterated APIs have not been shipped into the U.S.



We recognize that your SOP has been revised and submitted as a DRAFT revision of procedure #QCB.PKA00775, Version 5.1 for Handling of out of Specification Test Results

(OOS) during Chemical or Physical Test Methods, Microbiological Contamination and Endotoxin testing. However, most of it is in the German language. Please submit an English

translation once it is approved. Also include with your written response to this letter, the revised corporate GMP Directive CMS D08-50-01-1, for Handling of Out-of-Specification Results.



The inspection reported that your analysts had been trained to average passing and OOS results, and to report the average passing results. Please submit the translated training records for all analysts demonstrating that they have been trained in your new revised procedures.



Additionally, please submit your finished product sampling procedure and your scientific rationale for this procedure.



3. The Quality Unit failed to maintain responsibility and authority to review and conduct investigations. Your firm failed to conduct adequate investigations that included

scientific justification to support conclusions. In addition, the investigations did not include proper corrective actions. For example:



a. Out-of-specification (OOS) results were disregarded, and no OOS investigations were conducted after obtaining individual OOS assay results during release and stability

testing of your APIs. Instead, the OOS and passing results were averaged to obtain a reportable result within-specification, as referenced in item 2 of this letter. Our

investigator documented two stability intervals where individual OOS stability sample results were averaged with within-specification stability results, and no OOS

investigation was conducted. Examples of this practice were observed during the forty-eight month stability interval (25°C/60%) for (b)(4) (Batch # (b)(4)) and Medroxy Progesterone Acetate, (b)(4) (Batch # (b)(4)). The first batch showed duplicate assay results of (b)(4) and (b)(4), with a specification of (b)(4). The second batch showed duplicate assay results of (b)(4) and (b)(4), with a specification of (b)(4).



Refer to FDA-483 Observation #4a. We disagree with your rationale and conclusion submitted in your response for the reasons stated above in items 1 and 2 of this letter.



b. Norethindrone Acetate (b)(4) lot # (b)(4) was rejected (for destruction) because it was found with levels of (b)(4) for the impurity (b)(4). Your firm did not conduct an investigation to determine a root cause for the high level of impurity. Refer to FDA-483 Observation #9.



Your response states that this high impurity was a single event, and from a scientific view it is very unlikely in the NETA process because the (b)(4) is much more stable due to the (b)(4) functionality. Please supply supporting documentation for your conclusion.



c. OOS investigations did not adequately determine root cause, or provide for corrective actions to prevent recurrence. Investigation report #s 87302220 and 87201360,

related to an out-of-specification (OOS) result in the polarimetry test, and an OOS result in the assay by potentiometer titration. These reports respectively concluded that the OOS result was caused by a weighing error, and by the (b)(4) solvent used to conduct the test. However, when our investigator reviewed and discussed the investigations with your firm's personnel, he discovered that the real root cause for the OOS result was the use of an incorrect test method, and an improperly executed procedure for the equilibration of the electrode in (b)(4) (not the solvent itself), respectively. No corrective action was addressed in the investigation. In addition, investigation report # 82190246, related to an out-of-specification result in the melting point test, concluded that the OOS result was caused by not having sufficient amount of sample in the capillary (filling sample technique). No corrective action was addressed and/or documented to correct and prevent recurrence. Refer to FDA-483 Observation #4c. Your response lacks explanation and documentation to support your conclusions.



Your April 7, 2009, written response reports that you are revising your OOS standard operating procedure (SOP) to emphasize the importance of conducting and documenting a

thorough investigation of all OOS test results, including determining root cause analysis and evaluation of corrective and preventative actions. Your response indicates that the SOP became effective and training was completed by May 2009. Provide copies of the translated revised procedure and training records.



Your written response should also include the corrective action under consideration, or implemented to address the OOS test result examples (a and c), cited on the FDA-483 under Observation 4, and FDA-483 Observation 9. Provide a description of the corrective actions for each example cited, along with expected dates of completion, as well as a more

comprehensive review to ensure the revised OOS SOP's overall adequacy.



4. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment. Refer to FDA-483 Observation #5. For example:



The inspection revealed that production equipment, specifically the surface of the (b)(4) on production vessel (b)(4), used in the manufacturing process of Ethinylestradiol API, was not maintained in a clean condition even though the equipment was labeled cleaned, and had been inspected and verified as cleaned by the Production Department Shift Supervisor. This (b)(4) is in direct contact with the product when inside the vessel. Your response lacks an explanation and documentation to support your conclusion that the operator may not have detected the brown residue, because the equipment was wet when examined.



In your response to this Warning Letter, explain where the "inorganic substance insoluble in water or inorganic solvents" that you identified as the residue originated from. Additionally, your response mentions that the residue was removed by flushing with diluted (b)(4). Explain if this procedure is part of your routine cleaning procedure, and if your routine cleaning procedure is capable of removing the residue.



The CGMP deviations identified above, or on the FDA-483 issued to your firm, are not to be considered an all-inclusive list of the deficiencies that may exist at your facility. FDA

inspections are audits, which are not intended to determine all CGMP deviations or violations that exist at a firm. If you wish to continue to ship your APIs to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.



Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm's compliance with CGMP, this office may recommend withholding approval of any new applications or supplements listing your firm as an API manufacturer. In addition, failure to correct these deficiencies may result in FDA denying entry of articles manufactured by your firm into the United States.  [emphasis added] The articles could be subject to refusal of admission pursuant to Section 801(a)(3) of the Act [21 U.S.C § 381(a)(3)],in that the methods and controls used in their manufacture do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B) of the Act [21 U.S.C § 351(a)(2)(B)].



Please respond to this letter, with requested documents translated in English, within thirty days of receipt, and identify your response with FEI# 3002808295. Please contact Denise DiGiulio, Compliance Officer, at the address and telephone number shown below, if you have any questions or concerns regarding this letter.”


In short, FDA is obviously concerned about the failure of Bayer to properly test ingredients used in Yaz and Yasmin that may then ultimately reach and harm consumers that take Yaz and / or Yasmin. 


DVT is one of the potential side effects of taking Yaz, Yasmin, and Ocella.  Here is more information on DVT from Wikipedia. 


We thank Wikipedia for the information below and encourage you to support their work.  Please see main article, Discussion Tab, Contributors List, etc., here:  


Deep vein thrombosis

From Wikipedia, the free encyclopedia

  (Redirected from DVT)

"DVT" redirects here. For other uses, see DVT (disambiguation).

Deep vein thrombosis

Classification and external resources

A deep vein thrombosis in the right leg. Note the swelling and redness.







Deep vein thrombosis (DVT) (also known as deep venous thrombosis or economy class syndrome) is the formation of a blood clot ("thrombus") in a deep vein. Deep vein thrombosis commonly affects the leg veins (such as the femoral vein or the popliteal vein) or the deep veins of the pelvis. Occasionally the veins of the arm are affected (such as in Paget-Schrötter disease). A DVT can occur without symptoms, but in many cases the affected extremity will be painful, swollen, red, and warm, and the superficial veins may be engorged. The most serious complication of a DVT is that the clot could dislodge and travel to the lungs, which is called a pulmonary embolism (PE). DVT is a medical emergency, so, all limb swellings, however trivial, should be regarded as a DVT until proven otherwise. Untreated lower extremity DVT has a 3% PE-related mortality rate. Deaths associated with upper extremity DVT are extremely rare.[1] A late complication of DVT is the post-thrombotic syndrome, which can manifest itself as edema, pain or discomfort and skin problems.
According to Virchow's triad, venous thrombosis occurs via three mechanisms: decreased flow rate of the blood, damage to the blood vessel wall and an increased tendency of the blood to clot (hypercoagulability). Several medical conditions can lead to DVT, such as compression of the veins, physical trauma, cancer, infections, certain inflammatory diseases and specific conditions such as stroke, heart failure or nephrotic syndrome. There are several factors which can increase a person's risk for DVT, including surgery, hospitalization, immobilization (such as when orthopedic casts are used, or during long-haul flights, leading to traveller's thrombosis), smoking, obesity, age, certain drugs (such as estrogen, or erythropoietin) and inborn tendencies to form clots known as thrombophilia (for example, in carriers of factor V Leiden). Women have an increased risk during pregnancy, if they are on oral contraceptives, and in the postnatal period, due to increased estrogen levels.
The most commonly used tests for the diagnosis of DVT are a blood test called D-dimers and doppler ultrasound of the affected veins. Sometimes, further testing is required to find the cause of the DVT. In specific cases, an attempt can be made to break down the clot (using thrombolytic agents). To prevent further accrual and formation of new clots with a risk of pulmonary embolism, anticoagulation (blood thinners) is advised (if not possible, an inferior vena cava filter may be used). Prevention of DVT is advised in many medical and surgical inpatients using anticoagulants, graduated compression stockings (also known as thromboembolic deterrent stockings) or intermittent pneumatic compression (IPC) devices.

     1 Signs and symptoms
 2 Cause 2.1 Traveller's thrombosis
3 Pathophysiology
 4 Diagnosis 4.1 Physical examination
 4.2 Probability scoring
 4.3 Blood tests

4.4 Imaging
5 Prevention 5.1 Medical inpatients
 5.2 Surgery patients
 5.3 Pregnancy
 5.4 Travellers
6 Management 6.1 Anticoagulation
 6.2 Thrombolysis
 6.3 Thrombectomy
 6.4 Compression stockings
 6.5 Compression Systems
 6.6 Inferior vena cava filter
 6.7 Hospitalization
7 Prognosis
 8 Epidemiology
 9 References
 10 External links

  Signs and symptoms
There may be no symptoms referable to the location of the DVT, but the classical symptoms of DVT include pain, swelling and redness of the leg and dilation of the surface veins. In up to 25% of all hospitalized patients, there may be some form of DVT, which often remains clinically inapparent (unless pulmonary embolism develops).
There are several techniques during physical examination to increase the detection of DVT, such as measuring the circumference of the affected and the contralateral limb at a fixed point (to objectivate edema), and palpating the venous tract, which is often tender. Physical examination is unreliable for excluding the diagnosis of deep vein thrombosis.
In phlegmasia alba dolens, the leg is pale and cool with a diminished arterial pulse caused by spasm. It usually results from acute occlusion of the iliac and femoral veins because of DVT.
In phlegmasia cerulea dolens, there is an acute and nearly total venous occlusion of the entire extremity outflow, including the iliac and femoral veins. The leg is usually painful, cyanosed (blue from lack of oxygen) and edematous (filled with fluid). Venous gangrene may supervene.
It is vital that the possibility of pulmonary embolism be included in the history, as this may warrant further investigation (see pulmonary embolism).
A careful history has to be taken considering risk factors (see below), including the use of estrogen-containing methods of hormonal contraception, recent long-haul flying, intravenous drug use and a history of miscarriage (which is a feature of several disorders that can also cause thrombosis). In the case of long-haul flying, recent studies have shown that risk of DVT is higher in travellers who smoke, are obese, or are currently taking contraceptive pills.[2] A family history can reveal a hereditary factor in the development of DVT. Approximately 35 percent of DVT patients have at least one hereditary thrombophilia, including deficiencies in the anticoagulation factors protein C, protein S, antithrombin, or mutations in the factor V and prothrombin genes.[3]
The most common risk factors are recent surgery or hospitalization.[4][5] 40% of these patients did not receive heparin prophylaxis. Other risk factors include advanced age, obesity, infection, immobilization, use of combined (estrogen-containing) forms of hormonal contraception, tobacco usage and air travel ("economy class syndrome", a combination of immobility and relative dehydration).[5][6] Thrombophilia (tendency to develop thrombosis) often expresses itself with recurrent thromboses.
  Traveller's thrombosis
Traveller's thrombosis is the occurrence of deep vein thrombosis in travellers.[7][8] The term economy class syndrome has also been used to describe this.[9] Traveller's Thrombosis is most commonly reported in people who have travelled long distances by aircraft and who are already at an increased risk of thrombosis. A deep venous thrombosis can lead to the fatal complication of pulmonary embolism. Although all these diseases had been recognised for a long time,[10][11] the possibility of litigation against airline companies brought them into the limelight when this syndrome was reported.
The mechanism for thrombosis in travellers is probably due to a combination of immobilisation, dehydration and underlying risk factors. Additional environmental factors during air travel may also play a role.[12][13] Although the problem has been specifically related to air travel, it would appear that the problem is linked to immobility and that all travellers, including travellers by bus, train and car, are equally at risk.[14]
Patients with diseases that predispose them to thrombosis, such as antiphospholipid syndrome or cancer, are at a much greater risk. The highest risk groups include the elderly, those suffering serious medical conditions such as cancer, those with recent orthopedic surgery (legs or knees) and pregnant women.[15] Some researchers believe that endurance-type athletes are a high risk group.[16]
The WRIGHT (World Health Organisation Research Into Global Hazards of Travel) project has investigated the association between travel and venous thromboembolism (VTE), a term which covers deep vein thrombosis and/or pulmonary embolism (PE).[17] This has reported that the risk of VTE approximately doubles after a long–haul flight (>4 hours) and also with other forms of travel where travellers are exposed to prolonged seated immobility. Risk increases with the duration of the travel and also in passengers having other known risk factors of VTE.
An International Consensus Statement on Traveller's Thrombosis was published in 2008.[18]
Virchow's triad is a group of three factors known to affect clot formation: rate of flow (stasis), the consistency of the blood (high viscosity), and quality of the vessel wall (epithelial dysfunction). Virchow noted that more deep venous thrombosis occurred in the left leg than in the right and proposed compression of the left common iliac vein by the overlying right common iliac artery as the underlying cause (see May-Thurner syndrome).[19]
It is recognized that thrombi usually develop first in the calf veins, "growing" in the direction of flow of the vein. DVTs are distinguished as being above or below the popliteal vein. Very extensive DVTs can extend into the iliac veins or the inferior vena cava. The risk of pulmonary embolism is higher in the presence of more extensive clots.

Abdominal computed tomographic scan showing a common iliac vein thrombosis. The arrow indicates the filling defect in the vein visualised using radiocontrast.
The gold standard is intravenous venography, which involves injecting a peripheral vein of the affected limb with a contrast agent and taking X-rays, to reveal whether the venous supply has been obstructed. Because of its invasiveness, this test is rarely performed.
  Physical examination
Homans sign: Dorsiflexion of foot elicits pain in posterior calf. Pratt's sign: Squeezing of posterior calf elicits pain. However, these medical signs do not perform well and are not included in clinical prediction rules that combine best findings in order to diagnose DVT.[20]
  Probability scoring
In 2006, Scarvelis and Wells overviewed a set of clinical prediction rules for DVT,[21] on the heels of a widely adopted set of clinical criteria for pulmonary embolism.[22][23]
Wells score or criteria: (Possible score -2 to 9)
 1.Active cancer (treatment within last 6 months or palliative) +1 point
 2.Calf swelling >3 cm compared to other calf (measured 10 cm below tibial tuberosity) +1 point
 3.Collateral superficial veins (non-varicose) +1 point
 4.Pitting edema (confined to symptomatic leg) +1 point
 5.Previous documented DVT +1 point.
 6.Swelling of entire leg +1 point
 7.Localized pain along distribution of deep venous system +1 point
 8.Paralysis, paresis, or recent cast immobilization of lower extremities +1 point
 9.Recently bedridden > 3 days, or major surgery requiring regional or general anesthetic in past 4 weeks +1 point
 10.Alternative diagnosis at least as likely -2 points
 Score of 2 or higher — deep vein thrombosis is likely. Consider imaging the leg veins. Score of less than 2 — deep vein thrombosis is unlikely. Consider blood test such as d-dimer test to further rule out deep vein thrombosis.
  Blood tests
In a low-probability situation, current practice is to commence investigations by testing for D-dimer levels. This cross-linked fibrin degradation product is an indication that thrombosis is occurring, and that the blood clot is being dissolved by plasmin. A low D-dimer level should prompt other possible diagnoses (such as a ruptured Baker's cyst, if the patient is at sufficiently low clinical probability of DVT).[24][25]
  Other blood tests
Other blood tests usually performed at this point are[citation needed]:
 complete blood count
 Primary coagulation studies: PT, APTT, Fibrinogen
 liver enzymes
 renal function and electrolytes

An ultrasound image demonstrating a blood clot in the left common femoral vein.
Impedance plethysmography, Doppler ultrasonography, compression ultrasound scanning of the leg veins, combined with duplex measurements (to determine blood flow), can reveal a blood clot and its extent (i.e. whether it is below or above the knee). Duplex Ultrasonography, due to its high sensitivity, specificity and reproducibility, has replaced venography as the most widely used test in the evaluation of the disease. This test involves both a B mode image and Doppler flow analysis. It is most sensitive and specific for detecting proximal thrombi (in the popliteal and femoral veins), but substantially less so for distal thrombi (in the calf veins).[26]
  Medical inpatients
Clinical practice guidelines state:
 American College of Physicians (ACP) in 2011:[27][28] "ACP recommends assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence)."
 "ACP recommends pharmacologic prophylaxis with heparin or a related drug for venous thromboembolism in medical (including stroke) patients unless the assessed risk for bleeding outweighs the likely benefits (Grade: strong recommendation, moderate-quality evidence)."
 "ACP recommends against the use of mechanical prophylaxis with graduated compression stockings for prevention of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence)."
 "ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal venous thromboembolism prophylaxis regardless of risk."
American College of Chest Physicians (ACCP) in 2008:[15] "For acutely ill medical patients admitted to hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, we recommend thromboprophylaxis with LMWH (Grade 1A), LDUH (Grade 1A), or fondaparinux (Grade 1A)."

Enoxaparin or unfractionated heparin may be used.[29]
LMWH may be more effective than unfractionated heparin (UFH). If UFH is used, 5000 U 3 times daily may be more effective.[30]
Since publication of the ACCP guidelines, an additional randomized controlled trial[31] and meta-analysis[32] including the trial have been published. The meta-analysis concluded " Anticoagulant prophylaxis is effective in preventing symptomatic venous thromboembolism during anticoagulant prophylaxis in at-risk hospitalized medical patients. Additional research is needed to determine the risk for venous thromboembolism in these patients after prophylaxis has been stopped." With regards to which patients are at risk, most studies in the meta-analysis were of patients with New York Heart Association Functional Classification (NYHA) III-IV heart failure. Regarding patients at lesser risk of DVT, the trial above[31] and an earlier trial[33] are relevant yet inconclusive.
Since the ACCP guidelines, compression stockings have been studied for preventing clots in stroke patients.[34][35] In stroke patients, thigh-length stockings are more effective than knee stockings in the nonblinded CLOTS 2 randomized controlled trial[35] while thigh-length stockings were not better than no stockings in the CLOTS 1 nonblinded randomized controlled trial.[34] It is not clear why these two trials conflict.[36]
An effective preventative measure is early ambulation. [37]
Chronic renal dialysis patients may be at increased risk of thromboembolism,[38] but randomized controlled trials have not addressed the risk benefit of prophylaxis.
  Surgery patients
In patients who have undergone surgery, low molecular weight heparins (LMWH) are routinely administered to prevent thrombosis. LMWH can only currently be administered subcutaneously by injection. Prophylaxis for pregnant women who have a history of thrombosis may be limited to LMWH injections or may not be necessary if their risk factors are mainly temporary.
Early and regular ambulation (walking) is a treatment that predates anticoagulants and is still recognized and used today. Walking activates the body's muscle pumps, increasing venous velocity and preventing stasis. IPC devices have proven protective in bed- or chair-ridden patients at very high risk or with contraindications to heparins. IPC machines use air bladders that are wrapped around the thigh and/or calf. The bladders alternately inflate and deflate, squeezing the muscles and increasing blood velocity by as much as 500%. IPC machines have been proven effective on knee and hip surgery patients (a population with a risk as high as 80% with no prophylactic treatment) of developing DVT and PE.
See also: Hypercoagulability in pregnancy
The risk of deep vein thrombosis is increased in pregnancy because of a physiologically adaptive mechanism of increased hypercoagulability to prevent postpartum hemorrhage.[39] However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.[39]
While the general consensus among physicians is that the safety of the mother supersedes the safety of the developing fetus, changes in the anticoagulation regimen during pregnancy can be performed to minimize the risks to the developing fetus while maintaining therapeutic levels of anticoagulation in the mother.
The main issue with anticoagulation in pregnancy is that warfarin, the most commonly used anticoagulant in chronic administration, is known to have teratogenic effects on the fetus if administered in early pregnancy.[40][41]
A Cochrane review in 2006 concluded that passengers can expect a substantial reduction in the incidence of symptomless DVT and leg oedema if they wear compression stockings.[42] A randomised study in 2001 compared two sets of long haul airline passengers over the age of 50; one set wore MediUK mediven travel compression hosiery, while the other did not. The passengers were all scanned and blood tested to check for the incidence of DVT. The results showed that asymptomatic DVT occurred in 10% of the passengers who did not wear compression socks, whilst the group wearing compression had no DVTs. The authors concluded that wearing elastic compression hosiery reduces the incidence of DVT in long haul airline passengers. However it is worth noting that an asymptomatic DVT incidence of 10% is much higher than the expected symptomatic rate (alternatively estimated at less than 0.25%[43]) and wearing compression stockings was also associated with symptomatic superficial thrombophlebitis in 4%.[44]
Plane travellers who travel on the window seat have double risk of DVT.[45]
Prevention consists of adequate hydration (drinking, abstaining from alcoholic beverages and caffeine), moving around and calf muscle exercises.[8] Any traveller with significant risk factors should seek medical advice and be considered for prophylaxis. Aspirin alone is not recommended.[15] Severe risk for thrombosis can prompt a physician to prescribe injections with low molecular weight heparin (LMWH), a form of prophylaxis already in common use in hospital patients.[15]
Anticoagulation is the usual treatment for DVT. In general, patients are initiated on a brief course (i.e., less than a week) of heparin treatment while they start on a 3- to 6-month course of warfarin (or related vitamin K inhibitors). Low molecular weight heparin (LMWH) is preferred,[46] though unfractionated heparin is given in patients who have a contraindication to LMWH (e.g., renal failure or imminent need for invasive procedure). In patients who have had recurrent DVTs (two or more), anticoagulation is generally "life-long." The Cochrane Collaboration has meta-analyzed the risk and benefits of prolonged anti-coagulation.[47] Once the thrombosis is treated with RBC-thinning agents, the affected area has a fair chance of returning to its normal proportions. However, thinning agents do not lessen the chance of embolism to the pulmonary or coronary arteries. Thus, while the area affected with deep venous thrombosis (i.e. the legs) may cease coagulation, pulmonary embolism is still as possible. In a 2008 Cochrane review, it was found that anticoagulation used in combination with leg compression is a more effective therapy than anticoagulation alone.[48]
An abnormal D-dimer level at the end of treatment might signal the need for continued treatment among patients with a first unprovoked proximal deep-vein thrombosis.[49]
Despite the fact that no one disputes this, based on a meta analysis done by the Cochrane Collaboration where they found only one randomized trial of anti coagulation vs placebo in the treatment of VTE in which there was no significant difference between the two.[50]
Current recommendations for initial treatment of acute DVT include initiation of a vitamin K antagonist (VKA) together with LMWH or UFH on the first treatment day.[51] Heparin may be discontinued when the international normalized ratio (INR) is stable and greater than 2.0. For the duration and intensity of treatment for acute DVT of the leg, the recommendations include the following:
 for patients with a first episode of DVT secondary to a transient (reversible) risk factor, long-term treatment with a VKA for 3 months.
 for patients with a first episode of idiopathic DVT, treatment with a VKA for at least 6 to 12 months. The dose of VKA is adjusted to maintain INR in the range of 2.0 to 3.0.
 for the prevention of the post-thrombotic syndrome, the use of an elastic compression stocking is recommended.
Thrombolysis is generally reserved for extensive clot, e.g. an iliofemoral thrombosis. Although a meta-analysis of randomized controlled trials by the Cochrane Collaboration shows improved outcomes with thrombolysis,[52] there may be an increase in serious bleeding complications. In July 2008, the American College of Chest Physicians (ACCP) published new evidence-based clinical guidelines for the treatment of venous thromboembolic (VTE) disease which for the first time suggested the use of pharmacomechanical thrombolysis in the treatment of certain cases of acute DVT. Complete 2008 ACCP VTE guidelines can be downloaded at no charge at: TheNewGuidelines.org
Thrombus can be removed with a mechanical thrombectomy device. Combination therapy that uses mechanical thrombectomy to deliver localized thrombolytics has recently received considerable attention as a treatment for DVT.
  Compression stockings
Elastic compression stockings should be routinely applied "beginning within 1 month of diagnosis of proximal DVT and continuing for a minimum of 1 year after diagnosis".[46] Starting within one week may be more effective.[53] They reduce the risk of postthrombotic syndrome.[54] The stockings in almost all trials were stronger than routine anti-embolism stockings and created either 20–30 mm Hg or 30–40 mm Hg. Most trials used knee-high stockings. A meta-analysis of randomized controlled trials by the Cochrane Collaboration showed reduced incidence of post-thrombotic syndrome.[55] The number needed to treat is relatively high, at 4 to 5 patients needing to have been treated to prevent one case of post-thrombotic syndrome.[56]
  Compression Systems
Intermittent pneumatic compression (IPC) can be of benefit to patients deemed to be at risk of deep vein thrombosis. IPC is an accepted treatment method for preventing blood clots or deep venous thromboses (DVTs) and complications of venous stasis in persons after trauma, orthopaedic surgery, neurosurgery, or in disabled persons who are unable to walk or mobilise effectively.
Intermittent pneumatic compression (IPC) uses an air pump to inflate and deflate an airtight bag wrapped around the leg. This technique is also used to stop blood clots developing during surgery. However, the review of trials found conflicting evidence about whether or not IPC is better than compression bandages and hosiery. Intermittent pneumatic compression (IPC) is better for healing leg ulcers than no compression but it is uncertain if it improves healing when bandages or hosiery are already used [57]
  Inferior vena cava filter
Inferior vena cava filter reduces pulmonary embolism[58] and is an option for patients with an absolute contraindiciation to anticoagulant treatment (e.g., cerebral hemorrhage) or those rare patients who have objectively documented recurrent PEs while on anticoagulation, an inferior vena cava filter (also referred to as a Greenfield filter) may prevent pulmonary embolisation of the leg clot. However these filters are themselves potential of thrombosis,[59] IVC filters are viewed as a temporizing measure for preventing life-threatening pulmonary embolism.[60]
Treatment at home is an option according to a meta-analysis by the Cochrane Collaboration.[61] Hospitalization should be considered in patients with more than two of the following risk factors as these patients may have more risk of complications during treatment[62]:
 bilateral DVT
 renal insufficiency
 low body weight (<70 kg/154 lbs)
 recent immobility
 chronic heart failure
Main article: Post-thrombotic syndrome
In the one to two year period after the initial development of symptoms of deep vein thrombosis (DVT), post-thrombotic syndrome occurs in between as little as a fifth, and as much as half of cases. A "severe" post-thrombotic syndrome likewise varies in frequency between a twentieth and a tenth of individuals diagnosed with DVT. This malady is sometimes characterized by varicose ulceration.[63]
DVTs occur in about 1 per 1000 persons per year. It is estimated that approximately 350,000 to 600,000 Americans each year suffer from DVT and pulmonary embolism and at least 100,000 deaths may be directly or indirectly related to these diseases.[64]
DVT is much less common in the pediatric population. About 1 in 100,000 people under the age of 18 experiences deep vein thrombosis, possibly due to a child's high rate of heartbeats per minute, relatively active lifestyle when compared with adults, and fewer comorbidities (e.g. malignancy).
In pregnant women, it has an incidence of 0.5 to 7 per 1,000 pregnancies, and is the second most common cause of maternal death in developed countries after bleeding.[65]
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  External links
 North American Thrombosis Forum
 "Antithrombotic and Thrombolytic Therapy, 8th Ed: ACCP Guidelines". Chest (American College of Chest Physicians) 133 (6 suppl b–C). June 2008.
 International Society on Thrombosis and Haemostasis
 DVT patient information


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