Yaz and Yasmin: Two Controversial Birth Control Pills


Yaz and Yasmin: Two controversial birth control pillsYaz and Yasmin the birth control pills has been in news for wrong reasons. Canada reported 23 deaths due to these pills women took.

 

The New York Times reported on the controversy surrounding Yaz and Yasmin, two popular birth control pills (BCPs). Part of the controversy stems from problematic marketing and manufacturing processes identified by the Food and Drug Administration. However, the principal concern is whether these medications increase the risk of blood clots.

To understand the safety issues, here’s a little background. Common estimates are that at baseline about 1 women in 10,000 will have a blood clot this year; that number increases to about 3 women in 10,000 if they’re taking BCPs. (Compare this to the fact that more than 50 women in 10,000 will get a blood clot due to pregnancy.) Since this is true for many BCPs, what’s so special about Yaz and Yasmin?

Like many BCPs, Yaz and Yasmin use both estrogens and progestins to prevent ovulation. However, unlike other BCPs, Yaz and Yasmin use a new progestin called drospirenone.
The research on drospirenone is contradictory: one study sponsored by the manufacturer found no increased risk in blood clots, while two studies by independent researchers found a slight increase in blood clots from drospirenone.

Let’s take a closer look at these studies that show an increased risk. A Danish study by Lidegaard, published in the British Medical Journal, examined women taking different types of oral contraceptives. As expected, they found that the pill increases the risk of blood clots, from an annual rate of 3 per 10,000 women to 6 per 10,000 women. What did they find specifically about drospirenone? Comparing drospirenone to levonorgestrel (a progestin found in other BCPs such as Alesse and Nordette), they found that annually, 5.5 women out of 10,000 on levonorgestrel BCPs had blood clots, while about 8 women out of 10,000 on drospirenone had blood clots. A similar increase was also found when other progestins (desogestrel and gestodene, found in OrthoCept, Mircette, and others) were compared to levonorgestrel.

The second study, done in the Netherlands by van Hylckama Vlieg, found similar results. Patients taking BCPs had higher rates of blood clots: in patients aged 30-40 years old, the annual rate of blood clots was 2 per 10,000 women in patients who didn’t use BCPs, and 10 per 10,000 women who did use BCPs. It was lower in women younger than 30 and slightly higher in women older than 40. While the authors don’t report their results in the same manner as the previous study, extrapolation from their data shows that drospirenone has an annual rate of 12 blood clots per 10,000 women aged 30-40. Desogestrel BCPs also had similar increased rates compared to baseline.

The bottom line from these studies: Yaz and Yasmin, which use drospirenone, have a slightly higher risk of blood clots than BCPs using levonorgestrel. This risk is not dramatically higher. Furthermore, other BCPs containing desogestrel and gestodene also have a slightly increased risk of blood clots compared to levonorgestrel.

If you’re weighing the risks and benefits of birth control, remember that BCPs decrease the risk of getting ovarian and endometrial cancer. Also they definitely decrease the medical risks associated with pregnancy! To counter those benefits, there are some risks in smokers–people who smoke face increased risks of breast cancer and heart attacks if they use BCPs. There is debate whether non-smokers have an increased risk of breast cancer and heart attacks while using BCPs, currently there is no consensus on these issues.

Yaz and Yasmin: Two controversial birth control pillsHealth Canada records indicate that at least 23 deaths and 600 adverse reactions have been reported among women taking the birth-control pills (BCPs) Yaz and Yasmin (Bayer) in that country.

News of the reports was first reported by the Canadian Broadcasting Corporation (CBC) and has been widely picked up by Canadian media. Adverse-reactions reports, reviewed by heartwire, show that a total of 333 distinct cases, including 15 deaths, were collected for Yasmin and 267 for Yaz, including eight deaths. The Health Canada database includes adverse reports collected between 2007 and February 28, 2013.

The most common categories of adverse reports for both products are nervous system, vascular, and respiratory/thoracic/mediastinal disorders, but cardiac disorders were not infrequently listed. For Yasmin, cardiac disorders are listed as the primary system organ class in 4.1% of cases; for Yaz, that number was 6.6%.

The pills already carry a label warning that BCPs containing drospirenone—a synthetic progestin produced by Bayer—carry a risk of venous thromboembolism that is 1.5 to three times higher than seen with other birth-control pills. That estimate comes from a review Health Canada conducted in 2011; the agency issued a letter to physicians with its conclusions at the time. The FDA added a warning to drospirenone BCP labels in 2012.

In response to media reports on these adverse-event reports, Health Canada has reiterated that adverse-reaction reports do not necessarily mean that the product caused the adverse event. The agency has issued a statement saying, "At this time, it is Health Canada's view that the benefits of Yaz and Yasmin continue to outweigh the risks, when used according to Health Canada's approved labelling instructions. Health Canada has been monitoring the safety of contraceptive pills on an on-going basis, as it does for all drugs on the market, and is continuing to review the safety of all oral and non-oral hormonal contraceptives, including Yasmin and Yaz."


According to the Globe and Mail, the Society of Obstetricians and Gynaecologists of Canada is also urging against an overreaction . "Adverse events are very different from attributable events, and the latter is the number you need," the Globe quotes Dr Jennifer Blake, the society's CEO. "We are advising that there are no new data and . . . that the pills are safe and effective."

In April, Canadian courts certified the first class-action lawsuit against Bayer on behalf of women taking Yaz and Yasmin; at least 13 other class-action suits are pending across the country. The Globe reports that Bayer's report to shareholders in 2012 indicated that it had paid out $1.2 billion in settlements in thousands of US lawsuits. Bayer maintains the pills are safe and effective when used as directed.

Yaz, Yasmin and, its generic equivalent, Ocella (drospirenone/ethinyl estradiol) is a popular form of birth control. It is also marketed and prescribed for noncontraceptive purposes, including acne control and to treat premenstrual dysphoric disorder (PMDD). The FDA has found that the synthetic estrogen drospirenone contained in these medications can adversely affect the body's salt and water balance, which can lead to serious cardiac issues.

Cardiac Side Effects of Yaz

Yaz and Yasmin: Two controversial birth control pillsBecause Yaz and other medications containing drospirenone can result in high levels of potassium in the blood, also known as hyperkalemia, the side effects of Yaz can be extremely serious, and may include:

  • Heart attack

  • Heart palpitations

  • Stroke

  • Pulmonary embolism (PE)

  • Deep vein thrombosis

Yaz and Yasmin Side Effects

Yaz or Yasmin are different from other types of low dose birth control pills (BCP). Both Yaz and Yasmin contain a progestin hormone, drospirenone (DRSP), which is a synthetic progesterone.

On October 27, 2011, the FDA released its study findings on the risk of cardiovascular disease in combined hormonal contraceptives, such as Yaz or Yasmin. This study found that all the DRSP-containing BCPs, including Yaz and Yasmin, were associated with a significantly higher risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) compared to standard low dose birth control pills. This risk was particularly higher for women 10 to 34 years of age. Additionally, for women 35 to 55 years of age, DRSP was associated with a significantly higher risk of ischemic stroke or a heart attack.

Drospirenone (INN, USAN), also known as 1,2-dihydrospirorenone, is a synthetic hormone used in birth control pills. It is sold under the brand names Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, and Angeliq, all of which are combination products of drospirenone with an estrogen such as ethinylestradiol.

Drospirenone is an ingredient in some birth control pills and hormone replacement therapy. In combination with ethinyl estradiol it is used as contraception, and for women who want contraception it is also approved by the U.S. Food and Drug Administration (FDA) to treat moderate acne and premenstrual dysphoric disorder.

Adverse Effects

Women who take contraceptive pills containing drospirenone have a six- to sevenfold risk of developing thromboembolism (dangerous blood clots) compared to women who do not take anycontraceptive pill, and have twice the risk compared to women who take a contraceptive pill containing levonorgestrel.


Drospirenone can increase potassium to dangerous levels (hyperkalemia). It is likely to be especially dangerous or fatal for patients taking other drugs that also may increase potassium levels, such as ACE inhibitors, angiotensin-II receptor agonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs.

Yasmin was the first oral contraceptive that used drospirenone, and Yaz, the best-selling oral contraceptive in the US, also contains drospirenone. The labels for all contraceptives containing drospirenone warn that the drugs should not be used by women with hepatic dysfunction, renal insufficiency, or adrenal insufficiency. Like all oral contraceptives, these birth control pills should also not be used by women who smoke or have a history of DVT, stroke, or other blood clots.


While all oral contraceptives can increase the risk for venous thrombembolic events, including fatal blood clots, several studies have reported a greater risk for women taking contraceptives containing drospirenone. One study showed more than a 600 percent increased risk of these blood clots compared to non-users, compared to 360 percent higher for women taking birth control pills containing levonorgestrel, a different type of progesterone found in many generic birth control pills.

When the U.S. Food and Drug Administration (FDA) became concerned about the risks of drospirenone, they funded studies based on the medical records of more than 800,000 women taking oral contraceptives. They found that the risk of VTE, which includes dangerous and potentially fatal blood clots, was 93% higher for women who had been taking oral contraceptives made with drospirenone for only 3 months or less and 290% higher for women taking drospirenone oral contraceptives for 7–12 months, compared to women taking other types of oral contraceptives. To determine the exact risk for women of different ages and different circumstances, further study is warranted.


The FDA recently updated the label for contraceptives containing drospirenone to include warnings for stopping use prior to and after surgery, and to warn that contraceptives with drospirenone may have a higher risk of dangerous blood clots.

Pharmacology

Pharmacodynamics

Yaz and Yasmin: Two controversial birth control pillsDrospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has potent antimineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and has also been shown to possess mild antiandrogen activity.

 

The antimineralocorticoid properties exhibited by drospirenone promote sodium excretion and prevent water retention.
 

Pharmacokinetics

Drospirenone is taken orally with about 76% bioavailability. It is bound not by sex hormone-binding globulin or corticosteroid binding globulin, but by other serum proteins.
 

Metabolites have not been shown to be biologically active, show up in urine and feces, and are essentially completely excreted within 10 days.

Chemistry

It is an analog to spironolactone, with a molecular weight of 366.5 and the molecular formula C24H30O3.

Formulations

The compound is part of certain newer oral contraceptive formulations:

  • Yasmin contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet. It is indicated for the prevention of pregnancy in women who elect an oral contraceptive.

  • Yasminelle contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is used for contraception.

  • Yaz and Beyaz contain 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications.

  • Ocella contains 3 mg drospirenone and 30 mcg ethinylestradiol per tablet and is taken daily.

  • It has also been formulated in medication to manage menopausal symptoms using 0.5 mg drsp and 1 mg estradiol per day by oral application. This medication was introduced in the United States in 2007 as Angeliq.

Litigation and Regulatory Penalties

In 2008, a series of television commercials prompted the FDA to cite Bayer for overstating the approved uses of Yaz while failing to adequately warn viewers about the risks of the drug. Bayer was required to dispel the inaccurate information contained in those ads by creating new ads that clarified the drug's approved uses.


In September 2009, the FDA cited Bayer for sending out potentially low-quality batches of drosperinone. Bayer justified the shipments by explaining that they monitor the "average" quality of all shipments, not the quality of each individual batch.


As of August 2012, Bayer has notified its stockholders that there are more than 12,000 lawsuits against the company involving Yaz, Yasmin, and other oral contraceptives with drospirenone, and the company thus far has settled 1,977 cases for $402.6 million, for an average of $212,000 per case, while setting aside $610.5 million to settle the others.
 

The Allegations Include :

Glossing over risks associated with the products and overstating their approved uses in an effort to mislead users of Yaz and Yasmin into believing that the drugs were safe.


Failure to properly research the medication. Failing to recall the drug after post-marketing reports demonstrated that the risk of potentially life-threatening side effects of Yasmin and Yaz outweighed potential benefits that could be achieved via other available oral contraceptives. In October 2011 the CBC TV program Marketplace ran a segment discussing issues involved with the usage of Yaz/Yasmin.


 


Dated 15 June 2013

 

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