Rezulin News

From: Subject: Rezulin News Date: Tue, 12 Apr 2005 11:16:14 +0100 MIME-Version: 1.0 Content-Type: multipart/related; boundary="----=_NextPart_000_0000_01C53F51.09FB6B60"; type="text/html" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2800.1441 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C53F51.09FB6B60 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://web.archive.org/web/19991127133951/rezulin.com/bkgrnder2.html Rezulin News

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Rezulinnews = Home=20

Prescribing=20 Information

Link to=20 Warner-Lambert Site

Link = to ADA=20 Site

Link to FDA Site

WASHINGTON, D.C., March 26, 1999 =

The Incidence of Liver Effects in = Rezulin=20 Clinical Trials
and Postmarketing = Surveillance=20

The = liver, the=20 largest organ in the human body, is often = described as=20 the body's chemical processing factory, = performing=20 hundreds of complicated functions. The liver's = functions=20 vary from continuously refining and cleaning the = blood=20 of poisons and bacteria to manufacturing bile = necessary=20 for the digestion of fat in the diet.=20

Because the liver has the function of = processing=20 chemicals and drugs that enter the bloodstream, = it is=20 often susceptible to environmentally induced = injury. The=20 liver removes chemicals that are difficult for = the=20 kidneys to excrete and alters them so that they = can be=20 removed from the body through bile or urine, = sometimes=20 resulting in unstable toxic products. A feature = of the=20 liver is its general capability to grow new = liver cells=20 if damaged.=20

Some chemicals are intrinsic hepatotoxins and = are=20 known to cause liver injury. Other chemicals may = be=20 associated with an idiosyncratic reaction where = the=20 etiology is unknown. Rezulin is not an intrinsic = hepatotoxin. Intrinsic or predictable chemicals = result=20 in regular damage, following a certain level of = exposure=20 to a chemical, while idiosyncratic or = unpredictable=20 chemicals cause damage in only a small = percentage of=20 individuals who are exposed.=20

Liver damage can either be hepatocellular, = damaging=20 liver cells, or cholestatic, diminishing or = halting the=20 flow of bile. There are several ways to measure = the=20 presence of damage or inflammation in the liver. = The=20 most commonly used indicators of possible = hepatocellular=20 damage are alanine aminotransferase (ALT) and = aspartate=20 aminotransferase (AST) liver enzymes. Both of = these=20 enzymes are normally found in the liver and = filter into=20 the bloodstream when liver cells are injured. = ALT is a=20 more specific indicator of liver inflammation, = as AST is=20 also found in other organs such as the heart and = skeletal muscle. Bilirubin, the main bile = pigment in=20 humans, which when elevated causes the yellow=20 discoloration of the skin called jaundice, is = another=20 indicator of liver disease.=20

Rezulin and Liver Failure=20

Since its approval in January 1997, Rezulin = has been=20 prescribed for approximately 1.6 million = patients in the=20 United States. Like many medications, however, = it has=20 been associated with rare but serious adverse = events.=20

Following two reports of liver failure during = postmarketing surveillance, Parke-Davis, in = concert with=20 the U.S. Food and Drug Administration (FDA) = revised the=20 product labeling to include liver enzyme = monitoring=20 requirements. As a result of further label = revisions in=20 1997, and 1998, and increased physician and = patient=20 awareness, there has been an overall decline in = the=20 reported rate of severe liver events possibly = associated=20 with Rezulin and a significant reduction in = reports of=20 liver-related deaths among patients initiating = therapy=20 in 1998. By all objective measures, liver enzyme = monitoring has helped reduce the already rare = risk of=20 serious liver events allowing the vast majority = of type=20 2 diabetes patients to enjoy the important = benefits of=20 this therapy.=20

The following provides data about the = incidence of=20 adverse liver events during Rezulin clinical = trials and=20 in postmarketing surveillance since the approval = of=20 Rezulin in 1997.=20

Adverse Liver Events in the Clinical = Trials=20

During clinical trials in North America, 475 = patients=20 were treated with placebo and 2,510 patients = were=20 treated with Rezulin. Serum alanine = aminotransferase=20 (ALT) elevations >3 x ULN (upper limit of = normal)=20 were observed in 48 (1.9%) Rezulin-treated = patients and=20 3 (0.6%) placebo-treated patients.=20

The clinical protocol did not include rules = for=20 discontinuing therapy if liver enzyme elevations = occurred. However, therapy was discontinued for = 20 of=20 the 48 Rezulin-treated patients who had elevated = ALT=20 levels. Two of the 20 patients also developed = reversible=20 jaundice prior to discontinuation of therapy. = Both had=20 liver biopsies consistent with an idiosyncratic = drug=20 reaction. Each of these patients, including the = 2=20 jaundiced patients, normalized without any = permanent=20 clinical complications.=20

The onset of ALT elevations in the 20 = patients who=20 discontinued therapy was typically delayed; most = peak=20 ALT elevations occurred between 3 and 7 months = of=20 therapy. Only one of these patients developed = ALT >3=20 x ULN within 30 days of therapy initiation. = Serum ALT=20 levels promptly returned to baseline in most = patients=20 after therapy was discontinued.=20

Twenty other Rezulin-treated patients who had = ALT=20 elevations >3 x ULN continued their therapy = despite=20 the laboratory findings. Five of those patients = had=20 serum ALT >10 x ULN. Peak ALT elevations in = these=20 patients occurred between 2 and 18 months of = therapy.=20 Serum ALT levels returned to baseline and = normalized in=20 each of these patients despite continuation of = therapy.=20 The remaining 8 patients were found at the end = of study=20 to have ALT elevations >3 x ULN. Peak ALT = elevations=20 in these patients occurred between 2 and 9 = months of=20 therapy. Serum ALT levels returned to normal in = each of=20 these patients without clinical manifestation = and no=20 liver failures or liver-related deaths occurred = during=20 the clinical trials that preceded approval of = the new=20 drug application.=20

Postmarketing Surveillance=20

Postmarketing surveillance refers to the = continued=20 safety monitoring that occurs throughout the = life of a=20 drug following FDA approval. Many types of = adverse=20 events that are reported during the = postmarketing phase=20 only manifest themselves after a drug has been=20 prescribed to a much larger, more diverse = population=20 than exists in clinical trials with a limited = number of=20 patients.=20

Following the approval of Rezulin, = Parke-Davis=20 received 2 initial reports of liver failure. = Parke-Davis=20 initiated discussions with the FDA to evaluate = the=20 cases. After consultation with expert = hepatologists and=20 the FDA, Parke-Davis incorporated liver enzyme=20 monitoring requirements in the product labeling = in=20 October 1997.=20

As of March 5, 1999, Parke-Davis has received = 75=20 reports of deaths in the United States involving = some=20 mention of the liver, regardless of the = relationship of=20 the drug to the liver event or the outcome. The = FDA has=20 classified 26 reports as "possibly" or = "probably"=20 related to the drug, and it also has classified = nine=20 cases of transplant as possibly or probably = related to=20 the drug. Thirty-three of these reports were = from=20 spontaneous reports and 2 were from clinical = trials.=20

After continued analysis of the postmarketing = data by=20 Parke-Davis and the FDA, modifications were made = to the=20 monitoring requirements in December 1997 and = July 1998.=20 The Company also issued "Dear Doctor" letters = and=20 physician and patient communication programs = designed to=20 assure awareness of the importance of = monitoring. The=20 actions taken by Parke-Davis and the FDA since = October=20 1997 have dramatically decreased the reported = incidence=20 of serious adverse liver events. Thus, the = incidence of=20 reported liver failure leading to death or = transplant=20 was approximately 1 in 57,000 in patients = initiating=20 therapy since January 1998, shortly after the = boxed=20 warning was added to the label.=20

Rezulin may be used concomitantly with a = sulfonylurea=20 or insulin to improve glycemic control. Rezulin, = as=20 monotherapy, is indicated as an adjunct to diet = and=20 exercise to lower blood glucose in patients with = type 2=20 diabetes. Rezulin should not be used as = monotherapy in=20 patients previously well controlled on = sulfonylurea=20 therapy. For patients inadequately controlled = with a=20 sulfonylurea alone, Rezulin should be added to, = not=20 substituted for, the sulfonylurea.=20

Management of type 2 diabetes should also = include=20 diet control, weight loss and exercise. Rezulin = should=20 not be used in type 1 diabetes or for the = treatment of=20 diabetic ketoacidosis.=20

Rare cases of severe idiosyncratic adverse=20 hepatocellular events have been reported during = marketed=20 use (see Hepatic boxed WARNING in the full = prescribing=20 information). The hepatic event is usually = reversible,=20 but very rare cases of hepatic failure, leading = to death=20 or liver transplant, have been reported. These = events=20 have occurred after both short- and long-term = treatment.=20

Although liver enzyme monitoring cannot = completely=20 eliminate the potential for serious liver = problems, it=20 should help reduce the risk.=20

Rezulin patients should have liver enzyme = monitored=20 regularly. Serum transaminase levels should be = checked=20 at the start of therapy, monthly for the first = eight=20 months of therapy, every two months for the = remainder of=20 the first year of Rezulin therapy, and = periodically=20 thereafter.=20

In clinical studies, Rezulin was generally = well=20 tolerated. The incidence of withdrawals during = clinical=20 trials was similar for patients treated with = placebo or=20 Rezulin (4%). The most common adverse events = included=20 infection (22% placebo vs. 18% Rezulin), = headache (11%=20 placebo vs. 11% Rezulin), and pain (14% placebo = vs. 10%=20 Rezulin).=20

In premenopausal anovulatory patients with = insulin=20 resistance, Rezulin treatment may result in = resumption=20 of ovulation. These patients may be at risk for=20 pregnancy. Rezulin should not be used during = pregnancy=20 unless the potential benefits exceed the = potential risks=20 to the fetus.=20

Although an increase in plasma volume of 6% = to 8%=20 compared with placebo was observed in a 6-week = study of=20 troglitazone treatment in 24 normal volunteers, = there=20 was no increased incidence of adverse events = potentially=20 related to volume expansion (e.g. congestive = heart=20 failure) in controlled clinical trials for = Rezulin.=20 Patients with New York Heart Association (NYHA) = Class=20 III and IV cardiac status were not studied = during=20 clinical trials; therefore, Rezulin is not = indicated in=20 patients with NYHA Class III or IV cardiac = status unless=20 the expected benefit is believed to outweigh the = potential risk.=20

Please see accompanying full prescribing = information=20 for Rezulin.=20 =

=A91999 = Warner-Lambert=20 Company. All rights reserved. Use of and access to the information on = this site=20
are subject to the terms and conditions set out in the Agreement to = use the=20 Warner-Lambert Company Web sites.
Please review this Privacy Statement before = proceeding.=20
Created by Nethod, LLC. on = behalf of=20 the Warner-Lambert Company.
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