Drug Injury Watch

YAZ / Yasmin / Ocella / Beyaz / Safyral: Drug Safety Regulators Focus On Blood Clot Side Effects

EMA Orders New Warning About Risk Of Venous Thromboembolism, While FDA And Health Canada Begin Safety Review

(Posted by Tom Lamb at DrugInjuryWatch.com)

In recent months there has been a flurry of activity by drug safety regulators in North America as well as Europe concerning the progestin drospirenone and its apparent association with an increased risk of venous thromboembolism, e.g., pulmonary embolus, more commonly called pulmonary embolism, or pulmonary emboli (when there are more than a single blood clot causing a blockage of an artery in the lungs).

Drospirenone is used in combination with an estrogen in the following oral contraceptives:  YAZ (generics Gianvi and Loryna), Yasmin (generics Ocella, Syeda, and Zarah), Beyaz, and Safyral.
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Here is a quick survey of the actions taken by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and Health Canada.

The EMA announced on May 27, 2011 that it was updating the product information on oral contraceptives containing drospirenone (DRSP) regarding the risk of venous thromboembolism after a review of all available data, including some newly published data.

In more detail, from "Yasmin: risk of venous thromboembolism higher than levonorgestrel-containing pills", which was published in the June 2011 Drug Safety Update:

Epidemiological studies have shown that the risk of venous thromboembolism (VTE) for drospirenone-containing combined oral contraceptives (COCs), including Yasmin, is higher than for levonorgestrel-containing COCs (so-called ‘second generation’ pills)....

Yasmin contains drospirenone, a relatively new progestogen, and was first licensed in 2000. Evidence of the level of VTE risk associated with Yasmin has been accruing since then. The results of two early prospective cohort studies suggested no difference in risk of VTE between Yasmin and levonorgestrel-containing pills or ‘other’ COCs. However, in 2009, a Danish cohort study and a Dutch case-control study of the risk of VTE in association with a number of COCs found the risk with drospirenone-containing pills to be higher than the risk associated with levonorgestrel-containing pills. Two further studies were recently published: one using the US PharMetrics database and the other using the UK General Practice Research Database. Both corroborated the findings of the Danish and Dutch studies of an increased risk of VTE in association with use of drospirenone-containing pills relative to levonorgestrel-containing pills.

Recent unpublished re-analyses of data from the Danish study directly compared VTE risk for drospirenone-containing pills, levonorgestrel-containing pills, and desogestrel/gestodene-containing pills. These data strengthen and confirm the original findings, and have enabled firmer conclusions about the relative risk associated with drospirenone-containing pills.  [footnotes omitted]

The EMA action pertaining to the YAZ / Yasmin label change in Europe was quickly followed in the U.S. by the "FDA Drug Safety Communication: Safety Review of possible increased risk of blood clots with birth control pills containing drospirenone", which was issued on May 31, 2011:

The U.S. Food and Drug Administration (FDA) is informing the public about new information that is being assessed as part of FDA's ongoing safety review of birth control pills that contain drospirenone. This review will further evaluate the risk of blood clots in women who use these products....

A blood clot that forms in a deep vein in the body is called a deep vein thrombosis (DVT). A DVT is a rare side effect of taking birth control pills. A blood clot can break loose from the vein, move through the body to the lung, and cause a serious problem in the lung, called a pulmonary embolism (PE). This can lead to death.

Several days later came this press release, "Health Canada reviewing safety of drospirenone-containing oral contraceptives (Yasmin and Yaz) and risk of venous thromboembolism", issued on June 7, 2011:

Health Canada is informing health professionals and consumers, particularly women, that it is conducting an ongoing safety review of drospirenone-containing oral contraceptives to evaluate the potential for an increased risk of venous thromboembolism (VTE, which are blood clots) relative to other birth control pills.

We will watch the DRSP safety reviews being done by the FDA and Health Canada to see if either of these drug safety regulators order a stronger warning about blood clot side effects like pulmonary embolism (PE) and deep vein thrombosis (DVT) on the labels for YAZ, Yasmin, Ocella, Beyaz, and Safyral, similar to what the EMA did in Europe.
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Multaq Cardiovascular Deaths Overshadow Earlier Liver Injury Concerns For Drug Regulators

FDA Now Looking At Two-Fold Increase In CV Deaths, Strokes, And Heart Failure Hospitalizations From PALLAS Study Data 

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE:  "Multaq (dronedarone) - Information on Increase in Heart-Related Events in Patients with Permanent Atrial Fibrillation - Sanofi-aventis Canada Inc."  (8/4/11, Health Canada MedEffect e-Notice)

Multaq (dronedarone), Sanofi-aventis Canada Inc., must not be prescribed to patients with permanent atrial fibrillation. Early results from the PALLAS study suggest that patients with permanent atrial fibrillation on Multaq have more adverse cardiovascular events than patients who don't take Multaq.

For Health Professionals

For Health Public

(8/4/11)

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In mid-June 2011, soon after Sanofi-Aventis announced that it was discontinuing the late-stage PALLAS study, the European Medicines Agency (EMA) expanded its safety review of Multaq (dronedarone) to include cardiovascular side effects.

Previously, starting in January 2011, drug-induced liver injury had been the primary safety issue for Multaq.

Then, on July 21, 2011 the FDA issued this rather disturbing Safety Announcement about a two-fold increase in cardiovascular deaths associated with Multaq:

The U.S. Food and Drug Administration (FDA) is reviewing data from a clinical trial [the Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, sponsored by Sanofi Aventis (the maker of Multaq)] that was evaluating the effects of the antiarrhythmic drug Multaq (dronedarone) in patients with permanent atrial fibrillation. The study was stopped early after the data monitoring committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving Multaq compared to patients taking a placebo....

A critical question is whether and how the unfavorable results of the PALLAS study, obtained in patients with permanent atrial fibrillation, apply to patients who use Multaq for the approved indications (non-permanent atrial fibrillation, also known as paroxysmal or persistent atrial fibrillation)....

FDA has received and is currently reviewing preliminary results from the PALLAS study and will review the final results when they become available.

Source: "FDA Drug Safety Communication: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events"

In its July 21, 2011 press release, "European Medicines Agency updates on ongoing benefit-risk review of Multaq", the EMA said that it aimed to conclude its safety review of Multaq by September 2011.

The FDA, however, has set no target date for completing its review of the just recently available safety data from this PALLAS Multaq study.

Likewise, Health Canada, which is reviewing the heart-related safety of Multaq, also, has not set any date by which it might make its safety determination.

Together with those patients who use or used Multaq and concerned cardiologists around the country. who are looking for some safety-issue guidance, we will watch to see what the EMA, FDA, and Health Canada decide about the fate of Multaq.

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Sanofi Heart Medication Multaq Has Constantly Been On FDA's Radar During 2010 And 2011

Liver Failure, Renal Impairment, And Cardiovascular Problems Cited As Potential Signals Of Risk Involving Multaq

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE:  Health Canada announced on July 21, 2011 that it is reviewing the heart-related safety of Multaq.  See: Multaq: Health Canada reviewing heart-related risk

(7/21/11)

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We have reported previously here on some of the serious side effects that have been associated with Multaq (dronedarone):

Multaq Update: European Safety Review Expanded To Cardiovascular Side Effects Risk In July 2011

Sanofi-Aventis "Dear Doctor" Letter Will Warn Heart Drug Multaq Associated With Liver Failure

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A July 18, 2011 article by Robert Lowes, "New FDA Watch List Has Drug Making Fifth Straight Appearance", published online by Medscape (free subscription required) points out that Multaq was on the FDA's Potential Signals of Serious Risks/New Safety Information Identified by the Adverse Event Reporting System (AERS) list for all four quarters in 2010:

• The AERS watch list for the first quarter of 2010 cited potential signals of congestive heart failure for the drug. On February 22, 2011, the FDA revised the warnings and precautions section of dronedarone's label regarding patients with new or worsening heart failure during treatment to state that postmarketing cases of such problems have been reported....
• In the second quarter, AERS identified potential signals of torsade de pointes, a rare kind of ventricular tachycardia.
• The list for the third quarter of 2010 listed a potential signal for an interaction with warfarin that increases its anticoagulant effect. On March 21, 2011, the drug interactions section of dronedarone's label was changed to mention postmarketing cases of higher internal normalized ratio (INR) clotting times with or without bleeding events in patients taking warfarin....
• Potential signals of liver failure for dronedarone appeared in the watch list for the last 3 months of 2010. On February 11, 2011, the FDA changed the warnings and precautions section of the label to mention postmarketing cases of hepatocellular liver injury and acute liver failure, and the need to promptly discontinue dronedarone if such an injury is suspected....

In addition, Multaq was on this so-called "FDA watch list" for the first quarter of 2011, when the FDA detected potential safety signals concerning renal impairment and kidney failure.

Just as the FDA is continuing to evaluate these issues to determine the need for any regulatory action, we will continue to monitor the safety profile of Multaq.

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Multaq Update: European Safety Review Expanded To Cardiovascular Side Effects Risk In July 2011

EMA And FDA Already Had Sanofi Issue A "Dear Doctor" Letter About Liver Failure In January 2011

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE:  The FDA announced on July 21, 2011 that it is reviewing data from the PALLAS study which was stopped early after the data monitoring committee found a two-fold increase in death, as well as two-fold increases in stroke and hospitalization for heart failure in patients receiving Multaq compared to patients taking a placebo.  See: FDA Drug Safety Communication: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events

(7/21/11)

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On July 11, 2011 the European Medicines Agency (EMA) announced that it had expanded a safety review of Sanofi’s Multaq (dronedarone). This regulatory development came soon after the drug company’s announcement that it was discontinuing the late-stage PALLAS study.

From the EMA's July  11, 2011 press release, "European Medicines Agency reviews cardiovascular risk of Multaq":

The European Medicines Agency is reviewing the cardiovascular risk of the anti-arrhythmic medicine Multaq (dronedarone), from Sanofi Aventis. This follows the company’s announcement on 7 July 2011 of its discontinuation of the PALLAS study, because of the occurrence of severe cardiovascular events in some patients taking Multaq.

In the PALLAS study Multaq was being investigated in patients over 65 years of age with permanent atrial fibrillation....

The study was looking at the rate of major cardiovascular events (stroke or myocardial infarction) or hospitalisations due to cardiovascular events, or death. It found a higher rate of events and hospitalisations with Multaq when compared with placebo.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) started a review in January 2011 of the overall benefit-risk balance of Multaq following reports of severe liver injury. The scope of this review has now been extended to also assess new information from the PALLAS study and the CHMP will determine the need for any further action at its next meeting of 18-21 July 2011.

We had previously reported on the flurry of activity surrounding Multaq back in January 2011 with this post, "Sanofi-Aventis 'Dear Doctor' Letter Will Warn Heart Drug Multaq Associated With Liver Failure", and have been monitoring this emerging drug safety issue since that time.

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In their July 7, 2011 press release, "Sanofi Provides Multaq® Phase IIIb PALLAS Trial Update", the drug company tried to keep the more recently found cardiovascular side effects separate and apart from the earlier liver failure reports, stating: "The decision to terminate the study was not related to any hepatic adverse event."

The same Sanofi press release informed us "Currently approximately 400,000 patients have been treated with Multaq worldwide."

According to a July 11, 2011 Reuters news report by Ben Hirschler, "European regulators launch safety review of Sanofi’s Multaq":

Analysts see Multaq, which won approval from European medicines regulators in September 2009 and was approved in the United States in July 2009, as an important driver for Sanofi to see it through patents expiries on multibillion-dollar drugs like the cancer treatment Taxotere and the blood thinner Plavix.

Returning to our January 2011 post about Multaq and liver failure, we noted that the liver toxicity in addition to the cardiac side effects had caused renowned cardiologist Dr. Steven Nissen to express "concerns about the safety, efficacy and tolerability of dronedarone".

One wonders whether Sanofi will continue to promote Multaq or, instead, move to withdraw it from the market.  Only time will tell and, of course, we will let you know if there is a Multaq recall in the U.S. or in the European Union.

*****

P.S.  Multaq (dronedarone): Safety Labeling Change made in June 2011:

ADVERSE REACTION
Postmarketing Experience

• Respiratory: Postmarketing cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported.

 (7/14/11)
 

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P.S.  Potential Signals of Serious Risks/New Safety Information Identified by the Adverse Event Reporting System (AERS) between January - March 2011

Product Name: Active Ingredient (Trade) or Product Class: Multaq (dronedarone)

Potential Signal of a Serious Risk / New Safety Information: Renal impairment, Renal failure

Additional Information (as of May 31, 2011): FDA is continuing to evaluate these issues to determine the need for any regulatory action. 

(7/15/11)

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Chantix Anti-Smoking Pill: How Significant Is The Heart Risk; Should Chantix Be Recalled

Canadian Medical Journal Article Suggests That The June 2011 Label Change By FDA And Pfizer Is Not Sufficient Measure

(Posted by Tom Lamb at DrugInjuryWatch.com)

As some may recall, in mid-June 2011 the FDA issued these two items:

• Chantix (varenicline): Label Change - Risk of Certain Cardiovascular Adverse Events; and,
• FDA Drug Safety Communication: Chantix (varenicline) may increase the risk of certain cardiovascular adverse events in patients with cardiovascular disease.

A few weeks later the Canadian Medical Association Journal (CMAJ) published an article, "Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis", which raised two "new" concerns about this popular anti-smoking drug Chantix:  (1) whether the June 2011 cardiovascular, or heart, side effects risk warning label change is sufficient; and, (2) whether Chantix should be recalled by Pfizer and the FDA.

For an overview of this emerging drug-safety issue concerning Chantix (varenicline), we look to this July 4, 2011 Bloomberg news report, "Pfizer Addiction Pill Weighed by FDA After 72% Added Heart Risk":

Pfizer Inc. (PFE)’s anti-smoking pill Chantix may receive new warnings from U.S. regulators after a study released today found the drug increased the risk of hospitalizations for heart problems by 72 percent.

The report, led by researchers at Johns Hopkins University, analyzed 14 Pfizer-sponsored drug trials with 8,216 patients and found about one new heart attack or similar disorder for every 400 patients taking Chantix. The U.S. Food and Drug Administration is examining the study and may consider new warnings, Curtis Rosenbraugh, director of the agency’s office of drug evaluation, said in an interview....

An FDA staff review from 2006 shows the agency was aware of a potential link between Chantix and serious heart complications. At the time, two researchers were asked to independently review each reported heart problem to rule out cases that were incorrectly reported or not related to the drug. On closer inspection, one reviewer said there was a 16 percent added risk of heart problems with Chantix, while the second reviewer found an 8 percent decreased risk, according to the staff documents.

“We saw a swing going anywhere from favorable to unfavorable,” said the FDA’s Rosenbraugh. “When you get results like that it’s hard to draw a definitive conclusion. It’s not something we would label.

Label Uncertain

“Dr. Singh has added to what we have seen and is helping to define the picture better,” Rosenbraugh said. “I’m not sure until we can further evaluate the study whether it’s going to change the label or not, but I can assure you this is something we’re very concerned about and are taking very seriously.”

The senior author of this new Chantix medical journal article, Dr. Curt D. Furberg, a Wake Forest medical professor, was quoted in a July 4 New York Times article, "Study Links Smoking Drug to Cardiovascular Problems", as calling for a Chantix recall:  “I don’t see how the F.D.A. can leave Chantix on the market.”

Of course, we will continue to monitor this Chantix - heart risk safety issue and report significant developments, here.

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