Cholesterol Drug Zetia May Cause Serious Liver Injury Including Hepatitis And Liver Failure

Health Canada First Raised This Zetia Safety Issue In February 2005; News Reporter Discovers In December 2007 That Information Known By Merck and Schering-Plough About These Zetia Side Effects May Have Been Withheld

(Posted by Tom Lamb at DrugInjuryWatch.com)

Back on February 1, 2005 Health Canada posted on its web site a so-called "Dear Doctor" letter about Zetia (ezetimibe) -- called Ezetrol in Canada -- from Merck Frosst / Schering Pharmaceuticals that was intended to draw attention to some serious side effects associated with Zetia.  That 2005 Dear Doctor letter included the following:

The Warnings, Precautions, and Adverse Events sections are being updated to reflect the occurrence of the following adverse events in patients taking Ezetrol® (ezetimibe) alone or in combination with a statin:

• myalgia;
• rhabdomyolysis;
• hepatitis;
• acute pancreatitis;
• thrombocytopenia; and
• suspected interaction between Ezetrol® (ezetimibe) and warfarin 

In the U.S., however, Merck and Schering-Plough -- the drug companies responsible for Zetia, here -- chose not to send any corresponding Dear Doctor letter to American health care professionals, nor did the FDA mandate that they do so.

Returning to this 2005 Dear Doctor letter about Zetia, here is what was said about liver injuries to patients using Zetia and a statin drug (such as Zocor, Lipitor, Crestor, Lescol, Mevacor, or Pravachol):

Adverse hepatic events:

Elevations of liver transaminases and cases of hepatitis have been reported in patients treated with [Zetia]. Liver function monitoring is recommended when therapy with [Zetia] is initiated in patients treated or about to begin treatment with a statin.

Health care professionals should be aware that the use of [Zetia] in combination with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of liver transaminases.

In the two years since this 2005 Dear Doctor letter about Zetia was sent by the Merck and Schering group in Canada there have been some case reports of serious liver injury in patients using Zetia and statins -- but for the most part Zetia-induced liver injury had been off-the-radar for most drug safety observers. 

Now we have some idea about why, perhaps, Zetia-induced liver injury side effects were not more widely known.

In a December 21, 2007 article, "Data About Zetia Risks Was Not Fully Revealed", New York Times (NYT) reporter Alex Berenson broke the story that Merck and Schering-Plough had conducted several studies of Zetia which, in fact, raised the possibility that Zetia can cause liver damage when used long-term with other statins -- but these drug companies decided not to publish the results of those Zetia studies.

In preparing for his December 2007 Zetia article, the Times' reporter Alex Berenson spoke to a drug company representative and some medical doctors about this reporter's discovery of unpublished research about Zetia and liver-related side effects. 

We'll start with comments from two doctors who spoke with Mr. Berenson about this emerging drug safety issue:

“You don’t want to have data missing,” said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. “When there have been adverse effects, when the benefits don’t look impressive, those are the trials that historically don’t make it to press.”...

“We keep telling people we want to practice evidence-based medicine, and what we keep finding out is that much of the evidence is obscured,” said Dr. Harlan Krumholz, a cardiologist at Yale, when told about the previously undisclosed studies. “There is important evidence, but it’s not in public view. It’s hidden from investigators.”

On the other side of things, the Schering-Plough representative had this to say :

A Schering executive, when asked by a reporter about the unpublished [Zetia] studies, confirmed their existence. But the executive, Dr. Robert J. Spiegel, said the companies had not considered the [Zetia] studies scientifically important enough to publish their findings. Some may eventually be published, he said.

"We’re pretty comfortable that people don’t have trouble tolerating Zetia,” said Dr. Spiegel, the chief medical officer of the Schering-Plough Research Institute, Kenilworth, N.J.  (Emphasis added.)

In his December 2007 NYT article Mr. Berenson provides some reasons, however, why doctors and patients may not want to go along with this "reassurance" from Schering's Dr. Spiegel:

Most of the studies about Zetia in which Merck and Schering have published the results covered periods of only 12 weeks — not enough time for liver problems to develop in most patients....

But the F.D.A.’s documents show that Merck and Schering conducted several other long-term trials of Zetia without releasing their findings.

Together those studies cover several thousand patients who took Zetia along with statins for one to two years. The statins include Lipitor and Crestor, as well as Zocor, which is usually prescribed generically as simvastatin and is the statin used in the Vytorin pill....

The companies’ own published studies have generally played down the risk of liver problems. But Dr. Mark Stolk, a gastroenterologist in the Netherlands, last year reported two cases of patients who had developed hepatitis, a liver disease, after taking Zetia alongside Lipitor. One of the patients has since died, Dr. Stolk said in an interview last month. While Zetia is safe for most patients, doctors should carefully monitor patients for liver damage, he said.

“I think other cases will emerge,” he said.

What does the FDA have to say about this news reporter's discovery of unpublished studies suggesting that Zetia can cause serious liver injury when taken with statins?  Mr. Berenson tells us: "The agency did not respond to requests for comment."

To be sure, we will be reporting further developments as more is learned about the safety of Zetia -- one way or the other.

P.S.  Given how NYT reporter Alex Berenson discovered that Merck and Schering-Plough failed to publish some studies about Zetia and liver damage, Ed Silverman timely posted "How To Find Documents On The FDA Site" on his Pharmalot blog:

This cheat sheet should help you find briefing documents - the reams of supporting paperwork submitted by a drugmaker when seeking FDA approval for its med. It was compiled by a professor and students at the Lake Erie College of Osteopathic Medicine’s School of Pharmacy and recently published in the letters section of The Annals of Pharmacotherapy.

Thanks Ed for this insight about how emerging drug-safety issues (like the NYT Zetia story) can be found and exposed.  (12/21/07)

P.S.   Dr. Aubrey Blumsohn, over at the Scientific Misconduct Blog, gives us his strongly worded opinion about the position asserted by Schering's medical director in the NY Times story about Zetia and Vytorin, which I have bolded above. 

In his post, "More problems with Ezetimibe (Zetia, Vytorin): Let there be light", Dr. Blumsohn writes:

... Dr. Spiegel, it's not your decision. When patients might die it's always "scientifically important".

In addition, Dr. Blumsohn provides links to some other articles about this emerging Zetia study data controversy.  (12/23/07)

Comments

[Tom Lamb]

I am sorry to hear about the loss of your mother but appreciate you sharing the circumstances with us.

Presuming the medical records show the change in diagnosis regarding the liver problem, this would be a difficult products liability case to make against Vytorin, i.e., alleging Vytorin caused the liver problem. If, however, there was an autopsy or some pathology report that contradicted what this doctor said when he changed his diagnosis, the case would be stronger.

To the extent that we can be of further assistance, please do not hesitate to contact me.

Tom Lamb

[Miranda]

My mother, age 57, died 9 weeks ago (Jan. 2008) following treatment throughout 2007 with the cholesterol reducing drug, Vytorin. Her physician initially diagnosed her as having chemically induced hepatitis, but 3 days prior to her passing, "revoked" that diagnosis, stating that if it were chemically induced, her levels would have returned to normal, and therfore, she was dying of crytogenic cirrhosis (of unknown origin) and it was not at all related to the drug. She died much too young, and all of her symptoms followed use of the drug Vytorin.

[Tom Lamb]

I appreciate you taking the time to let us know about what you experienced during the time that you were taking Zetia.

If you are diagnosed with any liver damage or some other condition which a doctor says is a Zetia side effect, please get back in touch with us.

Hopefully your condition will improve now that you are no longer taking Zetia.

Thanks for reading Drug Injury Watch.

Tom Lamb

[8janine6]

I have been taking Zetia(10 mgm) for over 6 months with short breaks when I was sick or took antibiotics. My gut has not been right since. I have had severe gastritis( NOT caused by bacteria) and recent bouts of severe crampy lower abdominal pain requiring 3 ER visits and a hospitalization for suspected diverticulitis. Antibiotics were tried with no effect. All extensive tests negative for that or any other reason. Surgeon called it IBS(for lack of another cause) but I never had anything this bad (I am 65). My prescribing doc said to stop the Zetia--and I am NOT going to take it again.
I heard similar complaints from a couple of others who took Zetia. I am slowly getting better.

[Tom Lamb]

I appreciate you taking the time to address your inquiry to me but I am not a doctor and, therefore, cannot determine whether your liver condition or the bacteria is related to Zetia and/or Vytorin.

I suggest you speak about this with the doctor(s) who prescribed these drugs to you or some other doctor at your next opportunity.

If the doctor determines one or both conditions are Zetia / Vytorin side effects, please let me know.

Thanks for reading Drug Injury Watch.

Tom Lamb

[pam]

I was wondering if I am taking vytorin if it would causes a bacteria called giradia and at one time i was told that i had something on my liver that it was caused by pain meds that had tylenol so i was cut back on the tylenol part of pain meds but at that time i was taking zetia and lipitor now take vytorin what should i be checked for

[Tom Lamb]

Thanks for sharing with us the details of your Zetia - Zocor drug interaction experience.

Insofar that Zetia and Zocor are the two drugs that make up Vytorin, people taking Vytorin should take interest in your report, also.

Were you diagnosed with rhabdomyolysis secondary to Zetia and Zocor?

I hope you let us know more about your adverse drug event as you learn it from your doctors.

Thanks for reading Drug Injury Watch.

Tom Lamb

[GEORGE M MAALOUF]

I JUST GOT OUT FROM HOSPITAL AFTER SPENDING SEVEN DAYS BECAUSE OF MUSCLE BREAKDOWN , I WAS ON ZOCOR 80 MG FOR A LONG TIME , NINE OR TEN YEARS , MY DOCTOR ADDED ZETIA TO HELP MY CHOLESTEROL , TWO MONTHS NOW DEC 22 I STARTED TO FEEL THE EXCESS PAIN , FATIGUE AND DIFFICULTY IN MOVEMENT AND JOINTS , DEC 26 I NOTICED RED /WINE COLOR IN MY URINE . AT THE HOSPITAL WE FOUND OUT THAT EVERY THING IN MY BLOOD WORK WAS WAY WAY OFF , I WAS ASKED HOW MUCH I WAS DRINKING ALCOHOL OR WHEN DID I STOP ,( I DO NOT DRINK OR SMOKE ) ANY WAY I AGONIZED FOR SIX DAYS AT HOSPITAL WITH NEEDLES AND TUBES IN MY ARMS FILLED WITH ANTIBIOTICS , POTASIUM ,MAGNIZIUM AND HEPPERIN .I WAS GIVEN MORPHENE FOR THE PAIN . GRADUALY MY URINE GOT LIGHTER AND FINALY NORMAL BY THE NEW YEAR JAN 3RD TO BE EXACT .TESTS THET WERE TAKEN ( CATSCAN , ULTRASOUND , SONOGRAM , MRI , CHEST AND ABDOMEN X RAYS . DIAGNOSED WITH DRUG INTERACTION .. ZOCOR AND ZETIA , I'M BACK ON COUMIDIN AND TESTING MY INR EVRY OTHER DAY , FOLLOW UP WITH DOCTOR ON THE 9TH OF JAN .. I STILL HAVE THE WEAKNESS IN MY MUZCLES AND JOINTS AND HAVING DIFFICULTY WITH DAILY ROUTINES , PUTTING ON PJ'S , SOX , SHOES , GETTING IN AND OUT OF BED , SITTING AND GETTING OUT OFF CHAIR ,BACK PAIN , KNEES GIVE OUT IF I BEND OR TRY TO TIE SHOE LACES , ETC ..I HOPE I WAS OF HELP TO SOMEONE OUT THERE , I WILL FOLLOW UP WITH COMMENTS AFTER SEIING MY DOCTOR AND CARDIOLOGIST ..

[Tom Lamb]

Your situation is a good example of how this arguable misconduct by Merck and Schering-Plough negatively affects the doctors' ability to practice "evidence-based medicine", as pointed out by Dr. Harlan Krumholz, the Yale cardiologist, in the NYT article about the withheld Zetia study data.

Hopefully this newly-discovered information will help your doctors diagnose correctly your medical condition and determine its cause.

Thanks for reading Drug Injury Watch.

Tom Lamb

[David E]

earlier this year my internist suspected I had become a diabetic, based in part by evidence of liver damage which was reasonably confirmed by an ultrasound scan.

The physician, not the original prescriber, knew I was taking both Zetia and a statin, generic Pravachol (pravastatin) but evidently he had no knowledge of the reported hidden findings which were the basis of this article.

I will be seeing another physician early next month and will express my serious concerns given the liver damage (not previously noted) and the possible conneciton with Zetia.

[Tom Lamb]

I much appreciate you taking the time to share this information concerning your wife's apparent side effects from using Exetrol / Zetia.

As this information about Zetia-induced liver damage is only now coming to light -- due to the December 21, 2007 investigative article by NYT reporter Alex Berenson -- we suspect that other patients will now be in a position to consider whether their abnormal liver function tests, hepatitis, and/or liver failure was possibly caused by Zetia / Exetrol.

Thanks for reading Drug Injury Watch.

Tom Lamb

[M.C.]

My wife who is 66 years of age and in good health, has been on Lipitor for 10 years without any undue incidents. Approx: 2 years ago, her cardiologist added Ezetrol along with the Lipitor to get her Cholesterol levels which were excellent to even lower numbers. A few months later her AST & ALT numbers were climbing steadily, and the Dr. cut her 40mg. Lipitor to 20mg. After further blood testing, the numbers were still rising, so Lipitor was reduced to 10mg. After 18 months her AST & ALT numbers were almost 700 (Canadian).

An ultrasound was ordered and they found the entire right liver lobe had atrophied. An MRI was done, and confirmed all the findings of the missing right liver lobe. Next a ultrasound needle liver biopsy was performed, and it was evident that she was suffering from chemically induced hepatitis.

After stopping the Lipitor & Ezetrol, in the 1st week the numbers went from almost 700 for both ALT & AST to 350, and today 10 days late, it dropped a further 200, proving conclusively on the effect of the two drugs.

Have you had any similar reports from others. I would be very interested to learn about their ordeals and how it was resolved.