Drug Injury Watch

2006 Case Report Indicating That Xenical (Orlistat) May Cause Substantial Acute Liver Injury

Medical Journal Letter To Editor Stated That Exact Mechanism Of Hepatotoxicity In Subject Patient Was Unknown

(Posted by Tom Lamb at DrugInjuryWatch.com)

As we reported, on August 24, 2009 the FDA issued its "Early Communication" notification about an ongoing safety review of the obesity drugs Xenical (orlistat 120 mg) and Alli (orlistat 60 mg).

While that announcement by the FDA was the first time some people had heard about possible serious liver-related side effects caused by Xenical and Alli, this safety issue is not new.

In August 2006 The American Journal of Medicine (AMJ) published online a Letter to the Editor item titled "Severe Hepatic Injury Caused by Orlistat" which presented a then-recent case of acute hepatic injury in a 15-year old woman who was using Xenical. 

From this August 2006 AMJ item:

A 15-year-old Thai woman without remarkable medical history had taken orlistat (120 mg three times daily) for 7 days because of concerns of obesity. One week later, the patient was admitted to an emergency hospital with abdominal pain, malaise, nausea, and diarrhea, and was transferred to our hospital the following day. She had no toxic habits and denied taking any other medications or herbal remedies.... The patient’s serum aspartate aminotransferase and alanine aminotransferase levels were surprisingly high at 8269 IU/L and 9976 IU/L....  The results of screening for viral hepatitis (hepatitis A, B, C, and E virus; cytomegalovirus; Epstein-Barr virus) and autoimmune markers (antinuclear antibodies and antimitochondrial antibodies) were all negative. Abdominal ultrasound, computed tomography, and magnetic resonance imaging all showed normal findings. The patient was given vitamin K intravenously for 5 days, and liver function test results normalized within 1 month.

Based on these findings, the treating physicians arrived at these determinations:

• The exact mechanism of hepatotoxicity in our patient is unknown, although the presence of low-grade fever, eosinophilia, elevated immunoglobulin-E level, and cytopenia indicates an immunoallergic reaction.

• In addition, the temporal association between the institution of orlistat and the onset of hepatic abnormalities, the resolution of symptoms and the improvement of abnormal liver function test results after the drug was stopped, and the absence of alternative explanations strongly suggest that orlistat caused her liver injury.

• The Clinical Diagnostic Scale4 also has indicated a probable relationship between acute hepatotoxicity and orlistat, which is in agreement with our report indicating that orlistat may cause substantial acute liver injury. [footnote omitted]

We will be watching to see if there is an increase in the number of MedWatch reports submitted to the FDA concerning about Xenical or Alli and serious liver injury including liver failure due, perhaps, to media coverage of the FDA's announcement in late August 2009 about its ongoing safety review of Xenical and Alli.

FDA Conducts A Self-Critical Analysis Of Its Early Communications (ECs) Program

There Was Apparently A Brief Discussion About Effect Of ECs At July 2009 Agency's Drug Safety Oversight Board Meeting

The Public Summary for the July 16, 2009 meeting of the FDA's Drug Safety Oversight Board includes the main points of what appears to be a self-critical analysis of the agency's relatively new Early Communications about Ongoing Safety Reviews (ECs) program.  In relevant part:

Follow-up actions to the 21 Early Communications released since 2007

The Executive Director of the DSB presented a follow-up on 21 ECs issued from August 2007 to July 2009. Elements of an EC were given along with a brief description of each EC, the projected date for follow-up, actual date of follow-up, and the follow-up actions. The following lessons were learned:

• The media’s and public’s reaction has been generally positive.
• FDA could improve upon their estimated timeframe for follow-up as it has been imprecise with a few of the issued ECs.
• Companies can be significantly affected by an EC despite FDA’s disclaimer (that states FDA has not reached a conclusion but is studying the potential safety issue) that accompanies the communication. 
• The words in our disclaimer are not easily understood and interpreted by some of the public.

The most recent ECs from the FDA is "Early Communication about an Ongoing Safety Review Orlistat (marketed as Alli and Xenical)", which was issued on August 24, 2004.

Our coverage of this FDA action on August 24 ran with the sub-headline "FDA Early Communication Makes Clear That No Definite Association Between Liver Injury And Orlistat Has Been Established At This Time".

The response from GlaxoSmithKline about this FDA notice about a safety review of Alli and Xenical, simply titled "GlaxoSmithKline Statement Confirming alli Safety", was issued on August 24, 2009.

We would be interested in hearing your opinion about the FDA's Early Communications about Ongoing Safety Reviews (ECs) program.

Some Users Of Alli And Xenical Have Developed Serious Liver Injury Including Liver Failure

FDA Early Communication Makes Clear That No Definite Association Between Liver Injury And Orlistat Has Been Established At This Time

(Posted by Tom Lamb at DrugInjuryWatch.com)

On May 22, 2009 we first reported that the FDA is investigating the obesity drugs Xenical and Alli for a possible link with liver damage.

About three months later, on August 24, 2009, the FDA issued its "Early Communication about an Ongoing Safety Review Orlistat (marketed as Alli and Xenical)".

From this August 2009 Early Communication about Alli and Xenical:

Between 1999 and October 2008, 32 reports of serious liver injury, including 6 cases of liver failure, in patients using orlistat were submitted to FDA’s Adverse Event Reporting System. Thirty of the 32 reports occurred outside the United States. The most commonly reported adverse events described in the 32 reports of serious liver injury were jaundice (yellowing of the skin or whites of the eyes), weakness, and abdominal pain. Hospitalization was reported in 27 of the 32 cases.

In addition to the 32 reported cases, this issue was discussed at the CDER Drug Safety Oversight Board in April 2009, and FDA is reviewing other data on suspected cases of liver injury submitted by the manufacturers of orlistat. FDA’s analysis of these data is ongoing and no definite association between liver injury and orlistat has been established at this time.

We will continue to monitor and report on the safety profile of Alli and Xenical.

If you are aware of any cases of drug-induced hepatitis, liver injury, or liver failure involving the use of Xenical or Alli, please let us know by submitting a Comment, below, or you can send me a private email.

YAZ And Yasmin May Have Higher Risk Of Venous Thrombosis Than Older Birth Control Pills

Recent Studies Find That New Progestin Drospirenone Has 1.7 Times Increased Risk Of Developing Blood Clots Compared To Levonorgestrel

(Posted by Tom Lamb at DrugInjuryWatch.com) 

_________________________________________________________________________________________

UPDATE:  "Bayer Affirms Safety Of YAZ / Yasmin And Refutes 2011 BMJ Articles About Risk Of Blood Clots"  

(4/25/11)
_________________________________________________________________________________________

For current information, visit the YAZ, Yasmin, Ocella, Gianvi, Zarah, Beyaz, and Safyral Information page at our Drug Injury Law web site for more recent developments regarding personal injury and wrongful death lawsuits that involve YAZ, Yasmin, Ocella, Gianvi, Zarah, Beyaz, and Safyral.
_________________________________________________________________________________________

Let's start with an August 13, 2009 MedPage Today article, "Thrombosis Risk with OCs Depends on Progestogen", from which we get this concise summary of the issue from Nick Dunn, MD, of the University of Southampton:

All of the more recent progestogens, possibly except norgestimate, now seem to be at a disadvantage with regard to venous thromboembolism.

This quote comes from Dr. Dunn's editorial, "Oral contraceptives and venous thromboembolism", which accompanied the following two articles published August 13, 2009 by the medical journal BMJ:

• "The venous thrombotic risk of oral contraceptives, effects of estrogen dose and progestogen type: results of the MEGA case-control study"; and,

• "Hormonal contraception and risk of venous thromboembolism: National follow-up study".

The MedPage Today article summarized the first BMJ Research article, above, as follows:

[T]he Dutch researchers conducted a case-control study among premenopausal women under 50 at six clinics in the Netherlands.

They enrolled 1,524 cases and 1,760 controls, with the primary outcome established as a first deep venous thrombosis or pulmonary embolism.

They found that oral contraceptives increased the risk of venous thrombosis five-fold compared with non-use (95% CI 4.2 to 5.8).

Using contraceptives that contained levonorgestrel carried a 3.6-fold increased risk of venous thrombosis (95% CI 2.9 to 4.6). But risk was higher for other types of progestogens:

• 5.6-fold for gestodene (95% CI 3.7 to 8.4)
• 6.3-fold for drospirenone (95% CI 2.9 to 13.7)
• 6.8-fold for cyproterone acetate (95% CI 4.7 to 10.0)
• 7.3-fold for desogestrel (95% CI 5.3 to 10.0)

Compared with levonorgestrel, the risk of thrombosis associated with other progestogens increased as follows:

• gestodene (OR 1.6, 95% CI 1.0 to 2.4)
• drospirenone (OR 1.7, 95% CI 0.7 to 3.9)
• desogestrel (OR 2.0, 95% CI 1.4 to 2.8)
• cyproterone acetate (OR 2.0, 95% CI 1.3 to 3.0)

Risk was also positively associated with estrogen dose. Compared with a 30-mcg dose, thrombotic risk decreased 20% with a 20-mcg dose (OR 0.8, 95% CI 0.5 to 1.2) and increased nearly twofold for a 50-mcg dose (OR 1.9, 95% CI 1.1 to 3.4).

They also found that the risk of venous thrombosis was highest during the first three months of use (OR 12.6, 95% CI 7.1 to 22.4).

The popular birth control pills YAZ and Yasmin both contain the progestin drospirenone (DRSP); they are differentiated by the amount of estrogen each contains -- YAZ has a 20-mcg dose while the older Yasmin has a 30-mcg dose (as does its generic equivalent Ocella).

For her August 14, 2009 article, "Women Should Take Safest Birth-Control Pill, Researchers Say", Bloomberg reporter Andrea Gerlin sought out the reaction of Bayer -- which makes YAZ and Yasmin, "the two biggest-selling contraceptives worldwide, according to IMS Health", she reports.  Here's all she was able to elicit from the drug company:

“We have not seen the data and can’t comment on it at this point in time and soon as we have seen it, we can evaluate it,” Bayer spokeswomen Friederike Lorenzen said in an interview yesterday. “Patient safety is of utmost importance for us.”

Likewise, we are concerned about the safety of women who use YAZ, Yasmin, and Ocella. 

We will continue to monitor medical journals and other authoritative sources for the latest findings about the safety of these three drospirenone-containing birth control pills.

P.S.  Excerpt from the Abstract for "Risk of venous thromboembolism among users of oral contraceptives: a review of two recently published studies"  (J Fam Plann Reprod Health Care, January 1, 2010):

CONCLUSION: The best evidence continues to suggest that the increased risk of VTE in OC users is a class effect, dependent on the estrogen dose and duration of use, and independent of the progestogen used.

(2/15/10)

A Theory Of How Yasmin Or YAZ Might Cause Pulmonary Embolism (PE) And Other Blood Clot Related Side Effects

Combination Of Ethinylestradiol And Drospirenone Increases Serum Copper, A Situation That Could Be Associated With Increased Cardiovascular Risk

(Posted by Tom Lamb at DrugInjuryWatch.com)

In the August 1, 2009 edition of the medical journal Contraception there was an article which offers one possible explanation about why Yasmin and YAZ might cause an increased risk of developing serious side effects involving blood clots, such as pulmonary embolism (PE), deep vein thrombosis (DVT), stroke or cerebrovascular accident (CVA), and heart attack or myocardial infarction (MI) -- any of which can cause death if not detected and treated promptly.

From the Abstract for this August 2009 article, "Effects of oral contraception with ethinylestradiol and drospirenone on oxidative stress in women 18-35 years old.":

• BACKGROUND: Oral contraceptives (OCs) with estrogens and progestins may affect oxidative stress (OS) status.
• STUDY DESIGN: A group of 32 women using oral contraceptives (OCU) containing 0.03 mg ethinylestradiol and 3 mg drospirenone [i.e., Yasmin and its generic equivalent Ocella] have been compared to a matched control group of 30 noncontraception users (NCU).
• CONCLUSIONS: The recently introduced combination of ethinylestradiol and drospirenone induced the heightening of lipid peroxidation correlated with high levels of copper, a situation that could be associated with increased cardiovascular risk.

This possible "causation" theory actually pre-dates Yasmin and YAZ -- which were approved by the FDA in 2001 and 2006, respectively -- as can be seen from this 1998 medical journal article, "Effect of oral contraceptive progestins on serum copper concentration.", which was published in the European Journal of Clinical Nutrition.  From the Abstract for that article:

• OBJECTIVES: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives.
• CONCLUSION: While elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives.

An example of a so-called "third generation" birth control method is the vaginal ring NuvaRing, which contains etonogestrel, a biologically active metabolite of desogestrel.  NuvaRing -- sometimes simply called "the Ring" -- has been associated with an increased risk of serious blood clot side effects like pulmonary embolism (PE), stroke, and even death.

Yasmin and YAZ are regarded as "fourth generation" birth control pills for the reasons explained by this part of a 2005 article, "Oral Contraceptives: Mode of Action & Dermatologic Applications: Antiandrogenic Effect of Oral Contraceptives", published online by Medscape (FREE registration required):

New progestins have been synthesized in the past decade with no intrinsic androgenic effects but potent antiandrogenic activity, including cyproterone acetate, chlormadinone acetate, and dienogest....

Another progestin is drospirenone [(DRSP)], derived from 17-α-spirolactone and pharmacologically resembling endogenous progesterone. It has both antiandrogenic and antimineralocorticoid activities. It is antiandrogenic by inhibiting ovarian androgen production like other progestins, and it also blocks androgen receptors in the skin.

Estrogen stimulates angiotensin synthesis and enhances aldosterone-mediated water and sodium retention, making it responsible for such unpleasant symptoms as bloating, breast tenderness, and weight gain.

Drospirenone [(DRSP)] counters estrogen effect by blocking the aldosterone receptor, thus being antimineralocorticoid. This unique progestin attenuates the aforementioned bothersome estrogenic effects that some women report with the use of OC. It is also reported to improve androgen-related skin disorders, including acne, hirsutism, and seborrhea. [footnote omitted]

Returning to the Conclusion from that 1998 medical journal article -- "Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives." -- in fact, there is an ongoing FDA-mandated safety study about YAZ which is intended to compare this fourth generation birth control pill containing drospirenone (DRSP) to other established oral contraceptives for the incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), heart attack (MI), and stroke (CVA).

In addition, we will likely learn more about the blood clot side effects risks of Yasmin and YAZ -- as well as what their maker, Bayer, knew about those risks, and when -- during the course of the increasing number of Yasmin, Ocella, and YAZ lawsuits being filed on behalf of women injured and the families of women killed while using these birth control pills.

WebMD List Of Symptoms For Serious Side Effects From Using Estrogen-Progestin Birth Control Methods

Important Safety Information For Women Who Are Currently Using YAZ / Yasmin / Ocella, NuvaRing, Or Ortho Evra For Contraception Or Hormone Replacement Therapy

(Posted by Tom Lamb at DrugInjuryWatch.com)

_____________________________________________________________________________

UPDATE: Our Focus Page on YAZ / Yasmin / Ocella has a complete collection of our articles about these birth control pills as well as selected news reports about YAZ, Yasmin, and Ocella.

____________________________________________________________________

UPDATE:  Our Focus Page on NuvaRing has a complete collection of our articles about this birth control device / method as well as selected news reports about NuvaRing.

_____________________________________________________________________________

For women who are using estrogen-progestin methods of birth control, here is some important information from WebMD's Birth Control Health Center about the symptoms of some serious, potentially fatal side effects:

The following symptoms, called ACHES, are rare but serious and should be reported to your doctor immediately.

Abdominal pain that is severe or persists may be a sign of blood clots (thrombophlebitis) in the pelvis, liver blood clots or tumors, or gallbladder disease.

Chest pain may be a sign of blood clots in the lungs (pulmonary embolism), heart attack, or heart disease. Smoking increases this risk.

Headaches that are severe may be a sign of stroke, migraine, or high blood pressure (hypertension). Smoking increases this risk.

Eye problems, such as blurred vision or loss of vision, may be a sign of migraine, blood clots in the eye, or a change in the shape of the cornea.

Severe leg pain or sudden swelling of one leg may be a sign of leg blood clots (thrombophlebitis) or deep vein thrombosis (DVT).

While blood-clot related side effects -- such as pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and heart attack -- have been associated with all estrogen-progestin methods of birth control to some extent, it has been alleged that a few drug companies have not warned women sufficiently about the degree of safety risks associated with their birth control products. 

In turn, in recent years numerous personal injury and wrongful death lawsuits have been filed on behalf of women claiming there was a "failure to warn", which is a type of products liability legal claim.

In particular, our law firm and other attorneys have filed lawsuits for women who developed these serious side effects -- PE, DVT, stroke, and heart attack -- after using the following birth control methods:

YAZ / Yasmin / Ocella:  Each of these oral contraceptive (OC) pills contain ethinyl estradiol and the new "fourth generation" progestin drospirenone (DRSP);

NuvaRing:  A vaginal ring used for contraception which contains ethinyl estradiol and etonogestrel, a metabolite of desogestrel; and,

Ortho Evra:  "The Patch" is a norelgestromin and ethinyl estradiol transdermal system, i.e., in the form of a skin patch worn on the body.

Several years ago we started handling these lawsuits for (1) women have been injured and (2) the families of those who have died from using one of these apparently unsafe birth control methods.  Unfortunately, we continue to hear from women and their families in these situations right up until earlier today.

If you have this type of possible personal injury or wrongful death case, we offer a confidential, no-cost, and no-obligation Case Evaluation service:

• YAZ / Yasmin / Ocella Case Evaluation

• NuvaRing Case Evaluation

• Ortho Evra Case Evaluation

All states have statutes of limitations that determine the time period allowed to file a birth control side effect lawsuit. The applicable statute of limitation, or deadline to file claims, varies from state to state, and the personal injury statute of limitation deadline can be different from the wrongful death statute of limitation deadline within the same state. For example, in some states a personal injury claim must be filed within 3 years from the date a birth control injury is diagnosed, while a wrongful death claim must be filed within 2 years from the date of a death. In some states, the statutes of limitations may be as short as 1 year from the date of diagnosis or death.

Because of these varying deadlines, you should not delay seeking a law firm to provide legal advice and legal representation if you or a family member suffered a serious adverse reaction from using YAZ / Yasmin / Ocella, NuvaRing, or Ortho Evra.

What Are Medication Errors And How Do These Medical Mistakes Tend To Happen

North Carolina State Board Leads Way As Regards Reporting Of Pharmacy-Associated Medication Mistakes

(Posted by Tom Lamb at DrugInjuryWatch.com)

QJM is a long-established, leading general medical journal. It focuses on internal medicine and publishes peer-reviewed articles which promote medical science and practice.

In the August 2009 edition of QJM is an article, "Medication errors: what they are, how they happen, and how to avoid them", which provides a good overview of the various aspects of a medication mistake.  Here are some fundamental points from the Abstract for this recent medical journal article:

• A medication error is a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient.

• Medication errors can occur in

-- deciding which medicine and dosage regimen to use (prescribing faults—irrational, inappropriate, and ineffective prescribing, underprescribing, overprescribing); writing the prescription (prescription errors);

-- manufacturing the formulation (wrong strength, contaminants or adulterants, wrong or misleading packaging);

-- dispensing the formulation (wrong drug, wrong formulation, wrong label);

-- administering or taking the medicine (wrong dose, wrong route, wrong frequency, wrong duration);

-- monitoring therapy (failing to alter therapy when required, erroneous alteration). 

[Note: Format of sentence was changed for easier reading.]

• [Medication errors] can be classified, using a psychological classification of errors, as knowledge-, rule-, action- and memory-based errors.

• Errors in prescribing include irrational, inappropriate, and ineffective prescribing, underprescribing and overprescribing (collectively called prescribing faults) and errors in writing the prescription (including illegibility).

Remarkable to me, at least, is that only one state, North Carolina, has a mandatory reporting requirement for medication errors that involve a pharmacist or pharmacy.

According to "What state boards are doing about medication errors", an online special article published July 1, 2009 by Drug Topics ("The Newsmagazine for Pharmacists"):

As of June 2009 it appears that North Carolina remains the only state that requires any consistent public reporting of pharmacy-associated medication errors. In North Carolina, pharmacists must report errors associated with deaths.

According to Jay Campbell, RPh, JD, executive director of the N.C. Board of Pharmacy in Chapel Hill, “The requirement is that one needs to report [an error] to the board of pharmacy if they have reason to believe that a dispensed drug caused or contributed to a death of a patient. It is not a mandatory reporting of serious errors, only a report of deaths. Some of the data [we gather] are made public, and some aren’t. We produce a spreadsheet of information and we scrub out certain things that are not public information,” he said.

Campbell explained to Drug Topics that the “reporting rule isn’t keyed to an error; it’s broader than that. [We require a report] even if a drug is dispensed as ordered, yet it contributed to a death. Sometimes there’s a need to investigate — especially in a hospital, where a patient may have come in with underlying problems. There does sometimes seem to be a temporal relationship.”

This Drug Topics article adds that the North Carolina state board receives on average 40 to 60 reports per year, and, according to Campbell:

In our experience, we have seen a disproportionate number of deaths with anticoagulant products. They are a tiny fraction of global dispensing, yet they have, over the years, represented about 20 percent of reports.

Previous Drug Injury Watch articles about this subject area can be found in the Medication Errors category archives.

Some Criteria To Determine A New Drug's Potential For Causing Severe Drug-Induced Liver Injury (DILI)

In July 2009 FDA Issues Updated Guidance For Industry Document Concerning DILI In Premarketing Clinical Evaluation

(Posted by Tom Lamb at DrugInjuryWatch.com)

In July 2009 the FDA issued a Guidance for Industry document intended for pharmaceutical companies developing new prescription drugs which explains how certain laboratory measurements obtained in clinical trials can be used to assess the new drug's potential to cause severe drug-induced liver injury (DILI).  Further, this FDA document describes how these measurements can be evaluated so as to distinguish whether or not the new drug is "sending" so-called signals of potential severe liver injury.

Liver damage is the most frequent safety-related cause for pulling drugs from the market, according to this July 2009 Guidance for Industry document, "Drug-Induced Liver Injury: Premarketing Clinical Evaluation" from the FDA, which updates a draft version which was issued in 2007.

From the Introduction part of this Guidance document:

This guidance is intended to assist the pharmaceutical industry and other investigators who are conducting new drug development in assessing the potential for a drug to cause severe liver injury (i.e., irreversible liver failure that is fatal or requires liver transplantation). In particular, the guidance addresses how laboratory measurements that signal the potential for such drug-induced liver injury (DILI) can be obtained and evaluated during drug development. This evaluation is important because most drugs that cause severe DILI do so infrequently; typical drug development databases with up to a few thousand subjects exposed to a new drug will not show any cases. Databases may, however, show evidence or signals of a drug’s potential for severe DILI if the clinical and laboratory data are properly evaluated for evidence of lesser injury that may not be severe, but may predict the ability to cause more severe injuries. This guidance describes an approach that can be used to distinguish signals of DILI that identify drugs likely to cause severe liver injury from signals that do not suggest such a potential. This guidance does not address issues of preclinical evaluation for signals of DILI, nor the detection and assessment of DILI after drug approval and marketing.  [footnote omitted]

This July 2009 Guidance for Industry document concludes with "Appendix A: Illustrative Examples of DILI", which includes a brief discussion about the regulatory history of Duract (bromfenac), Rezulin (troglitazone), and Exanta (ximelagatran), each of which were associated with drug-induced liver injury (DILI).