DIABETES TECHNOLOGY & THERAPEUTICSVolume 2, Number 2, 2000Mary Ann Liebert, Inc.

289

REZULIN® was removed from the market onMarch 21, 2000 at the request of the Food

and Drug Administration (FDA). This actionprompted a response from each of the threemanufacturers of thiazolidinediones that havebeen used in the United States. These compa-nies include Warner-Lambert (Rezulin),

Takeda Pharmaceuticals America, Inc. (Ac-tos®), and SmithKline Beecham (Avandia®).Each of the three companies had a differentperspective on the FDA’s request. A statementfrom the FDA, followed by a statement fromeach of these three pharmaceutical companiesfollows.

News from the FDA

Rezulin to Be Withdrawn from the Market

ROCKVILLE, MD, March 21, 2000—The FDAtoday asked the manufacturer of Rezulin (trogli-tazone), a drug used to treat type 2 diabetes mel-litus, to remove the product fromthe market. Thedrug’s manufacturer, Parke-Davis/Warner-Lambert, has agreed to FDA’s request.

The FDA took this action after its review ofrecent safety data on Rezulin and two similardrugs, rosiglitazone (Avandia) and pioglita-zone (Actos), showed that Rezulin is more toxicto the liver than the other two drugs. Data todate show that Avandia and Actos, both ap-proved in the past year, offer the same benefitsas Rezulin without the same risk.

“When considered as a whole, the premar-keting clinical data and postmarketing safetydata from Rezulin as compared to similar, al-ternative diabetes drugs indicate that contin-ued use of Rezulin now poses an unacceptablerisk to patients,” said Dr. Janet Woodcock, Di-rector of FDA’s Center for Drug Evaluation andResearch. “We are now confident that patientshave safer alternatives in this important classof diabetes drugs,” she added.

Severe liver toxicity has been known to oc-

cur with Rezulin since 1997. In consultationwith FDA, Parke-Davis has strengthened thedrug’s labeling several times and has recom-mended close monitoring of liver function inpatients taking Rezulin.

In March 1999, the FDA’s Endocrine andMetabolic Drugs Advisory Committee re-viewed the status of Rezulin and its risk of livertoxicity and recommended continued avail-ability of this drug in a select group of pa-tients—patients not well-controlled on otherdiabetes drugs.

Since then, the FDA has continued to activelymonitor adverse events associated with Rezu-lin, as well as Avandia and Actos. After up to9 months of marketing experience with thesetwo newer drugs, it has now become clear thatthese newer drugs have less risk of severe livertoxicity than Rezulin.

Patients using Rezulin are urged to contacttheir physicians for information about alterna-tive treatments. Patients should not discon-tinue taking Rezulin or other treatments for di-abetes without discussing alternative therapieswith their physicians.

MORRIS PLAINS, NJ, March 21, 2000—Warner-Lambert Company announced todaythat it is voluntarily discontinuing the sale ofRezulin (troglitazone) tablets, its therapy forthe treatment of type 2 diabetes, although theCompany continues to believe that the benefitsof the drug outweigh its associated risks.

Patients taking Rezulin should consult withtheir physicians as soon as possible to discussalternative therapies. Warner-Lambert willwork closely with the FDA and other con-stituencies to assure a safe and efficient transi-tion for patients as they switch to alternativetherapies.

The Company has always believed that it isessential for patients and physicians to receive

accurate and objective information regardingthe benefits and risks of Rezulin. It was for thisreason that Warner-Lambert requested a pub-lic meeting of the FDA’s expert Advisory Com-mittee. However, repeated media reports sen-sationalizing the risks associated with Rezulintherapy have created an environment in whichpatients and physicians are simply unable tomake well-informed decisions regarding thesafety and efficacy of Rezulin. Under these cir-cumstances, and after discussions this eveningwith the FDA, we have decided it is in the bestinterests of patients to discontinue marketingRezulin at this time.

NEWS FROM THE FDA290

Warner-Lambert Voluntarily Withdraws Rezulin

Actos (Pioglitazone HCL) Provides a Safe, Effective Alternative for Patients Formerly Taking Rezulin

LINCOLNSHIRE, IL, March 22, 2000—TakedaPharmaceuticals America, Inc., distributor ofACTOS (pioglitazone hydrochloride), and EliLilly and Company are providing continuity ofcare for patients with type 2 diabetes nowsearching for therapy alternatives in light of therecent withdrawal of Rezulin (troglitazone)from the U.S. market.

“First and foremost, we want to make surepatients are able to continue effective therapyfor this complex, chronic disorder,” said Wen-dell Cheatham, M.D., Medical Director forTakeda. “Thiazolidinediones (TZDs) are an ef-fective therapy option to treat an underlyingcause of type 2 diabetes-insulin resistance.”

Actos is the most recent addition to this classof insulin-sensitizing diabetes agents that re-duce insulin resistance in multiple tissues, in-cluding the muscle.

Takeda and Lilly are actively assisting physi-cians in changing patients’ therapy. The com-panies are increasing the number of profes-sional samples of Actos to physicians to enable

them to provide Actos to these patients they se-lect for continued use of an agent to reduce in-sulin resistance.

For patients with normal liver enzymes whoare transitioned from Rezulin to Actos, a 1-week washout period followed by a baselineliver enzyme evaluation is recommended.Takeda is also offering its Patient-AssistanceProgram to all qualifying patients in financialneed who want to make the transition.

Actos has the broadest indications of anyTZD and is always taken once daily, regardlessof dosage strength and meal schedule. Thismay help minimize the disruption associatedwith transitioning for patients who may be con-cerned about changing therapies and adoptingnew schedules.

As an adjunct to diet and exercise, ACTOS isapproved for use as monotherapy to lower bloodglucose and in combination therapy with insulin,sulfonylureas and metformin. In 1999, Rezulinwas prescribed for use with insulin 40 percent ofthe time and with a sulfonylurea 43% of the time.

Actos is the only TZD now available that is FDAapproved for use with these two therapies.

Since Actos became available to consumersin August 1999, there have been more than670,000 prescriptions dispensed to more than350,000 patients and Actos is now, based onnew prescriptions, the leading TZD among en-docrinologists.

In U.S. placebo-controlled clinical trials, theoccurrence of elevated liver enzymes in ac-tively treated patients was 0.26%, as comparedto 0.25% in Actos study participants who re-ceived placebo. The postmarketing occurrenceof abnormal liver tests has been consistent withthat suggested by the clinical findings.

People with type 2 diabetes often have hightriglyceride levels and low levels of HDL(good) cholesterol. These two abnormalitiesmay increase the risk for heart disease, espe-cially in patients with diabetes.

In clinical trials, compared with placebo, Ac-tos significantly decreased mean triglyceridelevels and increased mean HDL levels in bothmonotherapy and in combination with sul-fonylureas, metformin or insulin. In contrast,no significant change in mean total cholesterolor mean LDL (bad) cholesterol levels was seenwith Actos used either as monotherapy or incombination therapy, compared with placebo.

“Actos provides an effective way for thesepatients to maintain continuity of care. It’s anexcellent treatment option that not only tacklesinsulin resistance but also has shown effect inhelping to improve the most common lipid(blood fat) imbalance found in patients withtype 2 diabetes,” Cheatham said.

Type 2 diabetes develops when the bodyeither does not produce enough insulin ordoesn’t efficiently use the insulin it does pro-duce, a phenomenon known as insulin resis-tance. Most type 2 diabetes treatments work byeither increasing insulin levels or decreasingglucose production.

Actos, however, helps reduce the body’s re-sistance to insulin, which means that the bodyuses its own insulin more effectively. Type 2diabetes—the most common form of the dis-ease—affects more than 14 million Americans.It most often occurs in people over age 45, buthas been diagnosed even in children. Left un-

treated, it can lead to serious health complica-tions including blindness, heart disease, stroke,kidney failure, and limb amputation. All told,diabetes consumes approximately $98 billion inU.S. health care costs annually.

Actos is indicated as an adjunct to diet andexercise to improve glycemic control in pa-tients with type 2 diabetes. The majority of sideeffects reported during Actos clinical trialswere mild.

Those most commonly reported includedsymptoms of upper respiratory tract infection,headache, sinusitis, muscle pain, tooth disor-der, and sore throat. As observed with othermembers of this class of drugs, weight gain hasbeen noted. Additionally, mild to moderateedema and anemia have been reported in pa-tients taking Actos.

Actos should be used with caution in pa-tients with edema. Patients receiving Actos incombination with insulin or sulfonylureas maybe at risk for hypoglycemia, and a reduction inthe dose of insulin or sulfonylureas may be nec-essary. Occasionally, diabetes worsened dur-ing clinical trials. This occurred less frequentlywith Actos than with placebo.

There have been no reported cases of jaun-dice or liver failure associated with Actos usein U.S. placebo-controlled clinical trials. How-ever, because liver toxicity has been observedwith the earliest approved drug in the TZDclass, patients should obtain medical monitor-ing of liver enzyme levels (via a blood test)prior to the start of therapy, every 2 months forthe first year of therapy, and periodically there-after to monitor liver function. Actos shouldnot be initiated in patients exhibiting clinicalevidence of active liver disease.

Therapy with Actos, similar to other thiazo-lidinediones, may result in ovulation in somepremenopausal anovulatory women. As a re-sult, these patients may be at risk for pregnancywhile taking Actos and adequate contraceptionshould be recommended.

Administration of oral contraceptives hasnot been fully evaluated in patients beingtreated with Actos. Therefore, additional caution regarding coadministration of Actosand an oral contraceptive should be exer-cised.

NEWS FROM THE FDA 291

PHILADELPHIA, PA, March 24, 2000—SmithKline Beecham, maker of Avandia(rosiglitazone maleate), the most prescribeddrug in a novel class of oral antidiabetes agentscalled thiazolidinediones, also known as glita-zones, is working with doctors to help the tran-sition of patients taking Rezulin (troglitazone)to safer alternatives. In addition, the companywill be offering special services for patientswith type 2 diabetes to get more informationabout glitazones.

More than 700,000 patients have started tak-ing Avandia in the United States and more than2 million prescriptions have been written.Avandia is the most widely prescribed glita-zone among endocrinologists (physicians whospecialize in treating diabetes) and primarycare physicians. Avandia is approved in morethan 26 countries including, most recently,Canada, and has received a positive opinion inthe European Union. This class of drugs is im-portant because it both treats the symptoms oftype 2 diabetes and directly targets insulin re-sistance, an underlying cause of the disease.

“Avandia is a clear choice for patients whoneed to transition from Rezulin to another gli-tazone, which will allow them to continue ther-apy with a safer and effective treatment alter-native,” said David Krause, M.D., vicepresident and director, Clinical Research De-velopment and Medical Affairs at SmithKlineBeecham. “In addition, passing two millionprescriptions underscores the confidence phy-sicians have in Avandia and in the importantbenefits of this class of drugs.”

The product performance continues to sup-port first-line use due to its reductions in in-sulin resistance, durable improvement inglycemic control, favorable tolerability , and

competitive price. Avandia continues to have afavorable safety record. The postmarketing ad-verse event profile continues to be generallyconsistent with what was seen in clinical stud-ies and with that seen in the population withtype 2 diabetes.

Last year, Avandia received approval fromthe FDA for the treatment of type 2 diabetes asboth monotherapy and in combination withmetformin as an adjunct to diet and exercise.The FDA approval was based on a review ofdata from clinical studies involving more than4,500 patients with type 2 diabetes in whichAvandia was proven to be safe and effective.(Editor’s note: On April 3, 2000, SmithKlineBeecham announced that the FDA approvedthe Avandia for use as a type 2 diabetes treat-ment in combination with drugs of the sul-fonylurea class as an adjunct to diet and exer-cise.)

Because of rare liver problems seen withRezulin, liver tests are recommended in all pa-tients prior to initiation of therapy with Avan-dia and periodically thereafter. Avandia wasgenerally well-tolerated in clinical trials. Com-monly reported adverse events were upper res-piratory tract infections and headaches. As ob-served with other members of this class ofdrugs, improvements in glycemic control wereassociated with weight pain. Additionally, alow incidence of anemia and edema were re-ported.

—Compiled byDavid C. Klonoff, M.D.

Editor-in-Chief

E-mail: Klonoff@itsa.ucsf.edu

NEWS FROM THE FDA292

Avandia, a Leading Alternative for Rezulin Patients,Prescribed to More Than 700,000 Patients