fda consumer, september-october 2006 · jason d. brodsky assistant commissioner for external...

Mike Leavi t t

Secretary of Health and Human Services

Andrew C. von Eschenbach, M.D.Acting Commissioner of Food and Drugs

Jason D. BrodskyAssistant Commissioner for ExternalRelat ions

Raymond Formanek Jr. / Editor

Michael Ermarth / Art Director

Linda Bren, Micheiie Meadows,Carol Rados / Staff Writers

Lisa Latimer / Production Assistant

Cover: Photo Researchers

FDA on the internet: www.fda.gov

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Y[)kConsumerThe Magazine of the U.S. Food and Drug Administration

September-October 2006 • Vol. 40 No. 5

9 Benzene in BeveragesA recent FDA survey shows that benzene levels in soft drinks and other

beverages are not a safety concern for consumers.

11 Curbing Counterfeit DrugsThe FDA has announced steps to strengthen protections againstcounterfeit drugs.

Cover Story1 2 I n fl u e n z a : Va c c i n a t i o n S t i l l t h e B e s t P r o t e c t i o n

As influenza season approaches, government agencies are working tomake enough vaccine available to protect you.

20 Pain Drugs for Dogs: Be an Informed Pet OwnerNSAIDs are valuable drugs for controlling pain, but pet owners need towatch for mild-to-serious side effects.

27 Advancing Public Health Through PartnershipsThe FDA's collaborations with other organizations are essential forprotecting and promoting public health.

37 New Vaccine Prevents Cervical CancerThis new vaccine helps protect women against a life-threateningdisease.

38 Vaccine Approved for Shingles in Older PeopleThe FDA has licensed Zostavax, a new vaccine to reduce the risk ofshingles in older Americans.

2 0

Nonsteroidal anti-inflammatory drugs areincreasingly being used safely and effectively

to control pain in dogs.

w

9

An FDA survey indicates that benzene levels inbeverages should not be a concern for consumers.

2 7

Collaborations with other government agencies,health care providers, regulated industry, experts,and consumers are essential to the FDA.

FDA Consumer / September-October 2006 / 1

D E P A R T M E N T S

2 O b s e r v a t i o n s

2 U p d a t e s

40 FDA Consumer Quiz

Observat ions

Every year in the United States,an average of 5 percent to 20 percent of the population comes downwith seasonal influenza, accordingto the Centers for Disease Controland Prevent ion. Of that number,more than 200,000 people are hospitalized from influenza-relatedcomplications, and about 36,000people die from it.

Each year, the Food and Drug Administration clears aseasonal influenza vaccine formulation that protects people against the strains of influenza considered most likelyto strike the Northern Hemisphere. Distribution of influenza vaccine begins in the fall. About 100 million dosesof influenza vaccine are expected to be available for the2 0 0 6 - 2 0 0 7 s e a s o n — a r e c o r d n u m b e r .

The vaccine does not protect people against bird (avian)flu, which is caused by different strains of the virus. Scientists worldwide are working to develop vaccines that couldbe effective against avian influenza.

Public health officials urge those eligible for vaccinationagainst seasonal influenza to receive it and remind peoplethat although influenza vaccination begins in Septemberor October each year, vaccine continues to be available inNovember, December, and later, and that immunizationduring those months is beneficial. For an in-depth look atthe 2006-2007 influenza season, see our cover story titled"Influenza: Vaccination Still the Best Protection," beginning on page 12.

The FDA regulates products that represent almost 25 percent of all consumer spending. The total includes 80 percentof the nation's food supply and all human drugs, vaccines.

medical devices, cosmetics, tissues for transplantation,radiation-emitting equipment, and animal drugs.

In order to accomplish this challenging task, other government agencies, health care providers, regulated industry, experts at colleges and universities, and consumerscontribute their expertise and experiences to help the FDAtackle complex scientific issues.

"Our collaborations are an essential part of the FDA'slong-term strategy to promote and protect the publichealth," says Acting FDA Commissioner Andrew C. vonFschenbach, M.D. We take a look at how the FDA collaborates with other organizations and individuals in our feature story titled "Advancing Public Health Through Partnerships," beginning on page 27.

Nonsteroidal anti-inflammatory drugs (NSAIDs) developed in recent years are increasingly being used to safelyand effectively control symptoms of arthritis, includinginflammation, swelling, stiffness, and joint pain in dogs.The FDA considers approved NSAIDs to be safe and effective when used according to the label and when dog ownersare informed about common NSAID adverse reactions. Formore on the use of NSAIDs in dogs, see our feature titled"Pain Drugs for Dogs: Be an Informed Pet Owner," beginning on page 20.

We also take a look at a recent FDA survey that indicatesbenzene levels are not a safety concern for consumers, newmeasures taken by the FDA to protect people against counterfeit drugs, and a new vaccine that helps protect womenagainst cervical cancer.

Raymond Formanek jr.E d i t o r

Updates

Mercury and Seafood AdviceS t i l l C u r r e n t

The FDA and the U.S. EnvironmentalProtection Agency want consurhers toknow that a joint advisory concerningmercury in fish issued in 2004 remainsc u r r e n t .

The advisory titled "What You Needto Know About Mercury in Fish andShel lfish" conta ins recommendat ionsfor women who might become pregnant, women who are pregnant, nursing mothers, and young children.

The FDA and the FPA say that women

2 / FDA Consumer / September-October 2006

and young children should includefish and shellfish as a regular part oftheir diet. Both are an important partof a healthy diet and can contribute toheart health and to children's propergrowth and development. Nearly allfish and shel lfish, however, conta intraces of mercury.

Women and young children canreceive the benefits of eating fish andshellfish while reducing their exposureto the harmful effects of mercury byfollowing three recommendations:• Do not eat shark, swordfish, king

mackerel, or tilefish because they contain high levels of mercury.• Fat up to 12 ounces (two averagemeals) a week of a variety of fish andshellfish that are lower in mercury,such as shrimp, salmon, pollock, catfish, and canned light tuna. Albacoretuna has more mercury than cannedlight tuna, so when choosing your twomeals of fish and shellfish, you may eatup to six ounces (one average meal) ofalbacore tuna per week.• C h e c k l o c a l a d v i s o r i e s a b o u t t h e

safety of fish caught by family and

Acting FDA Commissioner Andrew C.von Eschenbach, M.D, (left), presentsU.S. Health and Human Services SecretaryMike Leavitt with the Commissioner's

Special Citation at the FDA's centennialcelebration of the Pure Food and DrugsAct of 1906.

More than 200 people, including formerCommissioners of Food and Drugs,representatives of consumer and tradegroups, FDA employees, and descendantsof Dr. Harvey W. Wiley, the scientist whoseearly support of food and drug regulationsearned him the t i t le of "Father of the

Pure Food and Drugs Act," attended theJune 30 event at the Harvey W. WileyFederal Building in College Park, Md. TheCentennial event also was telecast to all

FDA employees nationwide.

U.S. Department of Health and Human Services/Chris Smith

friends in your local lakes, rivers, andcoastal areas. If no advice is available,eat up to six ounces (one average meal)per week of fish you catch from localwaters, hut don't consume any otherfish during that week.• F o l l o w t h e s a m e r e c o m m e n d a t i o n s

when feeding fish and shellfish toyoung children, hut serve smaller port i o n s .

T h e F D A c o n t i n u e s t o t e s t fi s h a n d

shellfish for mercury and will updatethe advisory if there is a significantchange in the underlying scienceregarding the risks from methylmer-cury or the benefits from eating fish.

See www.cfsan.fda.gov/' dms/admehg3.h t m l f o r m o r e i n f o r m a t i o n .

Increasing the Availability ofG e n e r i c s

The FDA has approved the firstgeneric version ofZocor (simvastatin),an important step in the agency's effortto increase the availability of lower-costgeneric medications.

Simvastatin is recommended for use,

along with a diet restricted in saturatedfat and cholesterol, to treat high cholesterol and to reduce the amount of certain fatty substances in the blood suchas triglycerides and other lipids.

Zocor is a member of a drug classknown as statins. According to ther e s e a r c h fi r m I M S F l e a l t h , s t a t i n saccounted for $16 billion in U.S. salesin 2005. Zocor was the second most

widely prescribed statin."Simvastatin is a widely-used cho

lesterol lowering agent, and its genericversion can bring significant savingst o t h e m i l l i o n s o f A m e r i c a n s w i t h t h i s

disease," says Gary 1. Buehler, directorof the FDA's Office of Generic Drugs.

Simvastatin tablets are manufacturedby I VAX Pharmaceuticals Inc. of North-vale, N.J., and by Ranbaxy Pharmaceuticals Inc., Princeton, N.).

The FDA has also recently approvedthe first generic version of Zoloft tablets(sertraline), as well as a liquid concentrate (sertraline hydrochloride) versionof the product.

Sertral ine tablets are indicated for

the treatment of major depressive disorder (MDD) in adults, and the liquid concentrate is approved for thetreatment of MDD and some anxiety-related disorders. In 2005, Zoloft wasthe sixth highest-selling brand-namedrug in the United States, with retailsales totaling $2.6 billion.

Other first generic products recentlyapproved by the FDA are• Finasteride tablets (Proscar) for thetreatment of benign prostatic hypertrophy (BPH) in men with an enlargedprostate to improve symptoms byreducing the size of the prostate• Lamotrigine tablets (Lamictal) fortreating patients with seizures due toepilepsy.

The economic benefits of the FDA's

generic drug approval program aresignificant because generics can costa fraction of the price of brand-namedrugs and generic drugs representabout two-thirds of total prescript i on doses so ld i n t he Un i ted S ta tes i n

2004, according to IMS data on U.S.re ta i l sa les .


I Updates

The FDA Approves New Over-the-Counter Sunscreen

Anthelios SX, a sunscreen to be sold over-the-counter(OTC) for the prevention of sunburn and for protectionagainst ultraviolet B (UVB)and ultraviolet A (UVA) rays,has been approved by theF D A .

"While this product provides protection from harmful UVA and UVB rays, FDAc o n t i n u e s t o r e c o m m e n d t h a tin addition to using a suns c r e e n , c o n s u m e r s p r o t e c tthemselves from sun exposure by limiting time in thesun and wearing protectiveclothing," says Steven Galson,M.D., director of the FDA's Center for Drug Evaluation andResearch .

Anthelios SX, which has a sun protection factor (SPF) of 15,is a sunscreen product that contains a combination of threeactive ingredients. One of the ingredients is a new molecular

entity (NME), ecamsule. Ecamsule has not been marketedin the United States, but has been marketed in Europe and

Canada as Mexoryl SX since1 9 9 3 . T h e o t h e r t w o a c t i v e

ingredients, avobenzone andoctocrylene, are generally recognized as safe and effectiveu n d e r t h e c u r r e n t OTC m o n o

graph for sunscreens.The safety and efficacy data

f o r A n t h e l i o s S X i n c l u d e di n f o r m a t i o n f r o m 2 8 s t u d i e s

involving more than 2,500people, ranging in age from6 m o n t h s t o m o r e t h a n 6 5

years. Side effects reportedduring clinical studies were infrequent and not serious.The most common side effects in patients were acne, dermatitis, dry skin, eczema, abnormal redness, itching, skindiscomfort, and sunburn.

The product will be distributed by La Roche-Posay.

Getty Images

C o r r e c t i o n s

An article titled "A Focus on Vision,"on page 10 of the July-August 2006issue, referred to "the National ContactLens Enforcement Petition in 2003 thatstrongly encouraged the FDA to amendthe medical device laws to include regulation of all contact lenses." This petition actually encouraged FDA to enforcethe existing law more effectively, not toamend the law, which only Congresscan do. In 2005, Congress amendedthe Federal Food, Drug, and CosmeticAct to define noncorrective, decorativecontact lenses as medical devices.

An article tit led "Artificial Sweeteners; No Calories ... Sweet," on page 27of the July-August 2006 issue, incorrectly stated that the artificial sweetener saccharin is generally recognizedas safe. Saccharin was discovered in1879 and had been considered generally recognized as safe (CRAS) until1972, when it was removed from theCRAS list by the FDA.

Treatment for Hunter SyndromeApproved

The FDA has approved Elaprase(idursulfase), the first product for thetreatment of Hunter syndrome (Mucopolysaccharidosis 11, or MPS 11), arare inherited disease that can leadto premature death. Elaprase is a newmolecular entity, which is an activeingredient never before marketed inthe Un i t ed S ta tes .

Hunter syndrome, which usuallybecomes apparent in children ages 1 to3 years, is a disease in which the person'sbody is defective in producing a chemical called iduronate-2-sulfatase. Thischemical is needed to adequately breakdown complex sugars produced in thebody. Symptoms include growth delay,joint stiffness, and coarsening of facialfeatures. In severe cases, patients experience respiratory and cardiac problems,enlargement of the liver and spleen,neurological deficits, and death.

Approved in July 2006, Elaprase wasdesignated as an orphan product bythe FDA. Orphan products are generally developed to treat rare diseases

or condi t ions that affect fewer than200,000 people in the United States.The Orphan Drug Act provides a seven-year period of exclusive marketing tothe first sponsor who obtains marketing approval for a designated orphanproduct. Hunter syndrome is diagnosed in about 1 out of every 65,000to 132,000 births.

Elaprase was approved after a randomized, double-blind, placebo-controlled study of 96 patients with Huntersyndrome showed that the treatedparticipants had an improved capacity to walk.

Because of the potential for severehypersensitivity reactions, appropriate medical support should be readilyavailable when Elaprase is administered. Patients and their physicians areencouraged to participate in a voluntary Hunter Outcome Survey that hasbeen established to monitor and evaluate the safety and effects of long-termtreatment with Elaprase.

Elaprase is manufactured by ShireHuman Cenetic Therapies Inc., Cambridge, Mass.


Updates

Warning on BismacineThe FDA is warning consumers and

health care providers not to use a product called bismacine, also known aschromacine. The agency is investigating one report of a death and severalreports of injury related to the administration of the substance.

Bismacine, an injectable productprepared by druggists, has been usedby some to treat Lyme disease. But bismacine has not been approved by theFDA to treat Lyme disease or any otherd i s e a s e o r c o n d i t i o n .

Bismacine is not a pharmaceutical. It is suggested or administered by"alternative health" practitioners or bypeople claiming to be medical doctors.Bismacine contains high amounts ofbismuth, a heavy metal used in somemedications taken by mouth to treata b a c t e r i u m t h a t c a n c a u s e s t o m a c hulcers (Helicobacter pylori). It is notapproved for use by injection.

On April 20, 2006, one person diedas a result of treatment with bismacine,and on March 29, 2005, another person was hospitalized after receivinga b i s m a c i n e t r e a t m e n t . O t h e r s e r i o u s

adverse events have been reported.Possible effects of bismuth poisoning include cardiovascular collapse andkidney failure.

The FDA is advising consumers andhealth care providers not to use bismacine. Individuals who believe they havesuffered adverse events from receivingbismacine may wish to seek medicalattention. The agency is evaluating theproduct suppliers and will take additional action as appropriate.

Adverse react ions exper iencedwith the use of this product shouldbe reported to the FDA's MedWatchAdverse Event Reporting programonline at www.fda.gov/MedWatch/report.htm; by phone (800) FDA-1088 (332-1088); by returning FDA form 3500,which may be downloaded from www.fda.gov/MedWatch/getforms.htm; by mailto MedWatch, 5600 Fishers Lane, Rock-ville, MD 20852-9787; or by fax (800)FDA-0178 (332-0178).

F i rs t Treatment fo r Dement ia o fPark inson 's D isease

The FDA has approved Exelon (riv-astigmine tartrate) for the treatment ofmild-to-moderate dementia associatedwith Parkinson's disease, a disorder ofthe central nervous system. Exelon wasapproved previously for the treatmentof mi ld- to-moderate dement ia of theAlzheimer's type.

"It's been recognized for almost adecade that the dementia of patientsw i t h P a r k i n s o n ' s d i s e a s e d i f f e r s f r o m

the dementia of patients with Alzheimer's," says Steven Galson, M.D., director of the FDA's Center for Drug Evaluat ion and Research. "But unt i l now,t h e r e h a s b e e n n o t r e a t m e n t t h a t h a sbeen shown to be effective specifically for the dementia associated withParkinson's disease. Today's approvalof Exelon helps to fill this medicaln e e d . "

It is estimated that about 0.2 percentto 0.5 percent of people older than 65are affected by Parkinson's dementia and experience such symptoms asimpairments in executive function,memory, and attention. The approvalof Exelon for the treatment of Parkin

son's dementia is based on the resultsof a randomized, placebo-controlledclinical study with 541 patients whoshowed symptoms of mild-to-moderate dementia two years or later aftertheir diagnosis for Parkinson's disease.At the end of the 24-week trial, the condition of the Exelon-treated patients, asshown on a scale that measures mental processes, was significantly betterthan the condition of the patients onplacebo.

T h e u s e o f E x e l o n h a s b e e n a s s o c iated with significant gastrointestinaladverse reactions. In clinical trials, 47percent of the patients treated with thedrug developed nausea, and others onhigh doses of Exelon experienced significant weight loss. Other commonadverse events reported by patientson Exelon include vomiting, anorexia,dyspepsia, and loss of strength (asthenia). In some patients with Parkinson's disease, treatment with Exelonwas associated with a worsening oft r e m o r .

Exelon is manufactured by NovartisPharmaceutical Corp. in East Hanover,N . L

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1 Updates

Treatment for Wet Macular DegenerationThe FDA has approved Lucentis (ranibizumab injec

tion) for the treatment of people with wet (neovascular)age-related macular degeneration (AMD). Lucentis is thefirst treatment that, when taken monthly, can maintainthe vision of more than 90 percent of people with thistype of AMD, studies show.

Lucentis is a new molecular entity, meaning it contains an active substance that has never before beenapproved for marketing in any form in the United States.It is the first FDA-approved product to provide prescription information in a new, easy-to-read format that theagency unveiled in January 2006 for prescription drugpackage inserts.

"This approval is of great importance for the 155,000Americans who are diagnosed each year with AMD, ac o m m o n c a u s e o f s e v e r e a n d i r r e v e r s i b l e v i s i o n l o s s i nolder adults," says Acting Commissioner of Food andDrugs Andrew C. von Eschenbach, M.D.

AMD is a retinal disease and a major cause of blindnessin individuals older than 55. Wet AMD, which accountsfor 10 percent of all AMD, is responsible for 80 percentof the assoc ia ted v is ion loss .

Lucentis, a biologic product, is designed to block thegrowth of abnormal leaky blood vessels, which cause thevision loss in wet AMD. Lucentis is administered by injection into the eye. It was shown to be safe and effective in

According to the Institute of Medicine (lOM) of the National Academies,more than 7,000 deaths a year areattributable to medication errors.

The educational campaign focuseson eliminating the use of potentiallyconfusing abbreviations by health careprofessionals, medical students, medical writers, the pharmaceutical industry, and FDA employees.

"We recommend tha t ISMP 's l i s tof abbreviations, symbols and dosedesignations most often associatedwith medication errors be consideredwhenever medical information is communicated," says the ISMP's PresidentM i c h a e l C o h e n .

For campaign materials and moreinformation, see www.fda.govI cderJ drugfMedErrors and www.ismp.org/tools/abbrev i a t i o n s .

National Eye Institute

three mult icenter,r a n d o m i z e d s t u dies of people repr e s e n t a t i v e o f t h e

populat ion usually affected withA M D . I n c l i n i

cal trials, nearly95 percent ofthe part ic ipantsw h o r e c e i v e d a

monthly injection maintained their vision at 12 months,compared with about 60 percent of patients who receivedthe control treatment. About one-third of the trial participants had improved vision at 12 months.

The most commonly reported side effects includedred eye (conjunctival hemorrhage), eye pain, smallspecks in vision (floaters), increased eye pressure, andinflammation of the eye. Serious side effects, whichwere rare and often related to the injection procedure,included severe inflammation of the interior of the eye(endophthalmitis), intraocular inflammation, retinaldetachment, retinal tear, increased eye pressure, andt r a u m a t i c c a t a r a c t .

Lucentis is manufactured by Genentech Inc. in SouthSan Francisco, Calif.

Campaign to Reduce MedicationM i s t a k e s

The FDA and the Institute for SafeMedication Practices (ISMP) have

launched a nationwide education cam

paign for health professionals aimedat reducing medication mix-ups andmistakes caused by the use of unclear

medical abbreviat ions."Some abbreviations,

symbols and dose designations are frequentlymisinterpreted and leadt o m i s t a k e s t h a t r e s u l tin patient harm," saysActing Commissioner ofFood and Drugs AndrewC. von Eschenbach, M.D."This joint campaign willpromote safe practicesamong those who comm u n i c a t e m e d i c a l i n f o rmation to help avoid serious and even potentiallyfatal consequences ofm e d i c a t i o n e r r o r s . "


New HIV Trea tmentA new HIV protease inhibitor, Prez-

ista (darunavir), has been approvedfor adults whose HIV infection has notresponded to treatment with other anti-retroviral drugs. Prezista is approvedto be used with a low dose of ritonavir and with other act ive ant i-HIV

agents. Ritonavir, a protease inhibitorapproved in 1996, slows the breakdown of Prezista in the body, therebyincreasing the concentration of Prezistain the person's system.

"This approval offers new hope toHIV patients who too often urgentlyneed new therapies in order to maintain their health," says Acting Commissioner of Food and Drugs AndrewC. von Eschenbach, M.D. "This drug

is not a cure, but when combined withother standard therapies, it presentsone more major step in our effort tohelp patients combat the effects of thed i s e a s e . "

The accelerated approval was basedon evidence from two randomized,controlled studies comparing the safetyand effectiveness of a Prezista-ritona-v i r combinat ion wi th other r i tonavi r -boosted protease inhibitor combinations. Participants in both arms ofthese tr ials also used other anti-HIVagents (nucleoside reverse transcriptase inhibitors), with or without enfu-vir t ide, which inhibi ts the virus fromentering the cell.

In these studies, participants on aPrezista-ritonavir combination expe

rienced higher rates of reduction oftheir HIV viral load than those onother ritonavir-boosted protease inhibitor combinations. Seventy percent ofthose treated with the Prezista-ritonavir combination achieved a response,improving the treatment outcome,compared with 21 percent in a controlgroup at six months.

T h e m o s t c o m m o n s i d e e f f e c t s

reported by those on the Prezista-ritonavir regimen included diarrhea,nausea, and headache. About 7 percentof people on this combination therapyexperienced skin rashes.

P r e z i s t a i s m a n u f a c t u r e d f o r T i b o t e c

Inc., a division of Ortho Biotech Products L.P., Raritan, N.J., by JOLL, Gurabo,P u e r t o R i c o .

First Drug for Seasonal Depression

The FDA has approved the first drug for seasonal affective disorder (SAD). Wellbutrin XL (bupropion HCLextended-release tablets) previously was approved totreat major depressive disorder. It's now also approvedto prevent major depressive episodes in people with ahistory of SAD.

SAD is characterized by recurrent major depressive episodes that usually coincide with the seasonal decrease ofdaylight during autumn and winter. The depressive episodes can last up to six months. Although patients withSAD may have depressive episodes during other times ofthe year, the diagnosis of SAD requires that the numberof seasonal episodes substantially outnumber the non-seasonal episodes during the individual's lifetime.

A major depressive episode is defined as the presenceof five or more of the nine core symptoms of majordepression for at least two weeks. The symptoms include:depressed mood, loss of interest, weight loss or otherweight or appetite changes, insomnia or hypersomnia,agitation or psychomotor retardation, fatigue, feelingsof worthlessness or guilt, impaired concentration, andsuicidal thinking or behavior. One of the five symptomsmust be either depressed mood or loss of interest inactivities. Another essential feature of major depressionis the presence of significant distress or impairment insocial, occupational, or other important areas of functioning. A seasonal major depressive episode is definedby the identical features.

T h e e f f e c t i v e n e s s o f W e l lbutrin XL for the preventionof SAD episodes was established in three double-blind,

p lacebo-con t ro l l ed t r i a l sin adults with a history ofmajor depressive disorder ina u t u m n a n d w i n t e r . I n t h e s e

trials, the percentage of people who were depression-freea t t h e e n d o f t r e a t m e n t w a s

significantly higher for thoseo n W e l l b u t r i n X L t h a n f o r

those on placebo. For all three studies combined, theoverall rate of patients depression free at the end of treatment was 84 percent for those on Wellbutrin XL, compared with 72 percent for those on placebo.

Wellbutrin XL's labeling includes a "black box"warning concerning the increased risk of suicidalthoughts and behavior in pediatric patients treated withantidepressant medications. As with all antidepressants,Wellbutrin XL has a Medication Guide advising thatpediatric patients on antidepressants should be watchedclosely for these serious symptoms. It is important tonote that Wellbutrin XL is indicated only for patientswho meet strict diagnostic criteria of seasonal majordepressive episodes. Wellbutrin XL is manufactured byGlaxoSmithKline, Research Triangle Park, N.C.


Updates

Drug Approved for Late-Stage Cervical CancerThe FDA has approved a combination of Hycamtin (topotecan hydro

chloride) and cisplatin for use as the first drug treatment for womenwith late-stage cancer of the cervix when surgery or radiation therapy isunlikely to be effective. The approval is a new indication for Hycamtin,which was approved in 1996 for treating ovarian cancer and in 1998 forsmall cell lung cancer.

In the United States, there are an estimated 10,000 new cases of cervical cancer and about 3,700 related deaths each year. "We are making greatstrides in the fight against cervical cancer, a disease that, world wide, isthe second most common cancer in women," says Acting FDA Commissioner Andrew C. von Eschenbach, M.D. "This course of drug therapy isa potentially life-prolonging option for thousands of women."

The combination of Hycamtin and cisplatin is specifically indicated forwomen with Stage fVB (incurable), recurrent, or persistent cancer of thecervix that spreads to other organs and is not likely to respond to treatment with surgery or radiation.

Hycamtin is associated with a significant risk of neutropenia (a drop inwhite blood cell count), a condition which makes it more difficult for thebody to fight infections. Serious side effects also include thrombocytopenia, a decrease in blood platelets that can lead to excessive bleeding andanemia. Less serious side effects include nausea and vomiting. The incidences of neutropenia, anemia, and thrombocytopenia were significantlyincreased among patients receiving the combination treatment, comparedwith those receiving cisplatin alone, as were nausea and vomiting, inflammation of a mucous membrane (mucositis), rash, and liver toxicity.

Hycamtin is manufactured by GlaxoSmithKline, Research TrianglePark, N.C.

New Safety Information on KetekThe FDA has completed its safety assess

ment of the antibiotic Ketek (telithromy-cin) and is advising health practitionersand patients to be aware of rare but potentially serious health risks.

Ketek is indicated for the treatment ofacute exacerbation of chronic bronchitis,acute bacterial sinusitis, and community-acquired pneumonia, including pneumonia caused by resistant strep infections.The drug has been associated with rarecases of serious liver injury and liver failure, with four reported deaths and oneliver transplant after its use. The manufacturer, sanofi-aventis U.S. LLC of Bridge-water, N.J., is revising the drug labeling toaddress this safety concern.

Although it is difficult to determinethe exact frequency of Ketek-associatedadverse events on the basis of the FDA's

reporting systems, the agency has concluded that the drug's benefit to patientsfor the approved indications outweighs itsrisk, including the rare risk of liver failure,and supports its continued availability.

"We are advising both patients takingKetek and their doctors to be on the alertfor signs and symptoms of liver problems," says Steven Galson, M.D., directorof the FDA's Center for Drug Evaluationand Research. "Patients experiencingsuch signs or symptoms should discontinue Ketek and seek medical evaluation,which may include tests for liver function." The signs and symptoms of liverfailure include fatigue, malaise, loss ofappetite, nausea, yellow skin, and dark-colored ur ine.

T h e F D A w i l l c o n t i n u e t o e v a l u a t eKetek-associated safety issues and willtake further action, if warranted.

Company Agrees to CorrectProblems With Infusion Pumps

Baxter Healthcare Corp. and two ofits top corporate executives have signeda consent decree of condemnation andpermanent injunction for certain infusion pumps made by the firm. The company and executives have agreed to stopmanufacturing and distributing all models of the Colleague Volumetric InfusionPump and the Syndeo Patient Controlled Analgesic Syringe Pump withinthe United States until manufacturingdeficiencies are corrected and until thedevices are made in compliance withthe FDA's current good manufacturingpractice requirements and quality systemregulation for devices.

Infusion pumps are electronic devicesused to control the delivery of solutions and medications to patients. Theya r e u s e d i n s i t u a t i o n s i n w h i c h m e d i

cation must be given intravenously orthrough other routes for an extendedperiod of time.

"Infusion pumps deliver life-saving drugs and nutrition to thousandsof critically ill patients," says DanielSchultz, M.D., director of the FDA'sCenter for Devices and RadiologicalHealth. "But if they don't work properly, patients are put at risk. Baxterhas clearly had significant problemswith some of its infusion pumps. Withthis action, Baxter has agreed to correct those problems. FDA's goal is tosee that the necessary corrections aremade, that the public health is protected, and that users have access tosafe and effective pumps."

Under the consent decree, the FDAwill allow the firm to continue to provide routine maintenance, or to replacecomponents, parts, or accessories, forthe Colleague and Syndeo InfusionPumps that were already in the handsof customers before Oct. 12,2005. Baxter also is required to submit to the FDAan acceptable detailed corrective actionplan to bring these infusion pumpscurrently in use in the United Statesinto compliance with the Federal Food,Drug, and Cosmetic Act. ■


Benzene inBeverages

By Michelle Meadows

■ he Food and Drug

A d m i n i s t r a t i o n

is working withthe beverage industryto ensure that benzene

levels in soft drinks and

other beverages are aslow as possible. Benzene is a chemical used

in dyes and detergents,and in some plastics. It'salso released into the air

f rom automobi le emis

sions and results from

burning coal and oil.Benzene may be produced in soft drinks and

other beverages withcertain ingredient combinations. High levels ofbenzene in workplaceai r have caused cancer

i n wo rke rs .


The FDA has no regulatory limitsfor benzene in beverages other thanbott led water. The U.S. Environmental Protection Agency has establisheda maximum contaminant level forbenzene of 5 parts per billion (ppb) indrinking water. The FDA has adoptedthis level for bottled water as a quality standard. Based on results from arecent survey of soft drinks and otherbeverages conducted by the FDA's Center for Food Safety and Applied Nutrition (CFSAN), most beverage samplesanalyzed contained either no detectable benzene or levels below the 5 ppblimit for drinking water, and do notsuggest a safety concern, says Judith

"The presence of benzoates and vitamin C as ingredients in a productdoesn't mean that elevated levels ofbenzene have formed or will form,"Kidwell says.

A Recent SurveyIn November 2005, the FDA received

private laboratory results reporting lowlevels of benzene in a small number ofsoft drinks that contain benzoate preservatives and vitamin C. In responseto these findings, the FDA began collecting and analyzing samples of beverages with a focus on products that contain both benzoate and vitamin C.

From the start of the survey in

above 5 ppb in five of the beverageproducts tested; Crystal Light SunriseClassic Orange, Crush Pineapple, Safeway Select Diet Orange Soda, Aqua-Cal Strawberry Flavored Water Beverage, and Giant Light Cranberry JuiceC o c k t a i l .

A d d i t i o n a l A c t i o n sThe FDA has contacted those firms

whose products were found to contain more than 5 ppb benzene in theCFSAN survey. Manufacturers havereformulated the products to reduceor eliminate benzene, and some havesent samples to the CFSAN for analysis.Thus far, the CFSAN has tested a few

The FDA and industry initiated research anddiscovered that exposure to heat and light can stimulate theformation of low levels of benzene in some beverages that

contain both benzoate salts ... and vitamin C.

Kidwell, a consumer safety officer int h e C F S A N s O f fi c e o f F o o d A d d i t i v e

Safety.

How Benzene May Form inS o f t D r i n k s

In 1990, the FDA learned that benzene was present in some soft drinks.The FDA and industry initiated researchand discovered that exposure to heatand light can stimulate the format i o n o f l o w l e v e l s o f b e n z e n e i n s o m e

beverages that contain both benzoate salts, such as sodium benzoate orpotassium benzoate, and vitamin C(ascorbic acid).

Sodium benzoate or potassium benzoate may be added to beverages to prevent the growth of bacteria, yeasts, andmolds. Benzoate salts also are naturallypresent in some fruits and their juices,such as cranberries. Vitamin C maybenaturally present in beverages or addedto prevent spoilage or to provide addit i o n a l n u t r i e n t s .

November through April 2006, theF D A t e s t e d m o r e t h a n 1 0 0 s o f t d r i n k sand other beverages. Beverage samplesw e r e c o l l e c t e d f r o m r e t a i l s t o r e s i n

Maryland, Virginia, and Michigan. Thesurvey is not a reflection of the distribution of benzene in beverages in theU.S. food supply. The data cover a limited number of products and brands,and limited geographic areas. Eventhough the data are limited, Kidwellsays, the FDA believes that the resultsind i ca te t ha t benzene l eve l s a re no t a

safety concern for consumers. In May2006, the FDA released results of thesurvey through April 20, 2006.

Almost all the samples analyzed inthe CFSAN s survey contained eitherno benzene or levels below 5 ppb.' A n d b e n z e n e l e v e l s i n h u n d r e d s o f

samples tested by other governmentagencies and the beverage industryare consistent with CFSAN s findings,"Kidwell says.

T h e C F S A N f o u n d b e n z e n e l e v e l s

of the reformulated products providedby the manufacturers and found thatbenzene levels were less than 1 ppb;additional testing is ongoing.

T h e I n t e r n a t i o n a l C o u n c i l o f B e v e r

ages Associations and the AmericanBeverage Association have developedguidance for all beverage manufacturers on ways to minimize benzenef o r m a t i o n .

The FDA w i l l con t i nue to co l l ec t and

analyze beverage samples for the presence of benzene and will continue tofollow up with manufacturers as survey results warrant. "Once the FDA hascompleted its beverage survey we willd e t e r m i n e w h e t h e r f u r t h e r a c t i o n i s

necessary to protect the public health,"Kidwell says. ■

F o r M o r e I n f o r m a t i o n

Questions and Answers on Benzenein Beverageswww.cfsan.fda.govI ^dms lbenzqa.html


n June 2006, the Food and DrugAdministration's Counterfeit DrugTask Force released a new report

on ways to curb the growing problemof counterfeit drugs. The reportrecommends measures that emphasizecertain regulatory actions and the useof new technologies for safeguardingthe integrity of the drug supply in theUnited States.

"The adoption of the FDA Counter- fact, the FDA was encouraged by most quency identification (RFID), wouldfeit Drug Task Force s recommenda- drug stakeholders to allow the hold provide an electronic safety net fortions will further reduce the risk that to expire. Doing so also would pro- our nation s drug supply. RFID placescounterfeit products will enter the U.S. vide clarity in the drug supply chain electromagnetic chips and tags con-drug distribution system and reach regarding who is and is not required to taining a unique serial number ontopatients," says Acting FDA Commis- pass a pedigree. Continuing the hold cartons and individual drug products,sioner Andrew C. von Eschenbach, would allow the current confusion to This technology creates an e-pedigreeM.D. "We must remain vigilant in our continue and to further allow oppor- for tracking the movement of the drugefforts to ensure our nation's drug tunities for counterfeiting activity. The through the supply chain. The reportsupply is protected against an increas- hold expires in December and will not recommends that stakeholders con-i n g l y s o p h i s t i c a t e d c r i m i n a l e l e m e n t b e c o n t i n u e d . t i n u e t o w o r k e x p e d i t i o u s l y t o w a r dengaging in a dangerous type of com- Consistent with recommendations of this goal, and that their implementa-m e r c e . " t h e Ta s k F o r c e , t h e F D A a l s o a n n o u n c e d t i o n o f R F I D t e c h n o l o g y b e u s e d fi r s t

Among the new measures, the FDA that during 2007, its enforcement of on products most susceptible to coun-will fully implement regulations related the pedigree regulations will focus on terfeiting.to the Prescription Drug Marketing Act products most susceptible to counter- The new FDA report is largely basedof 1987, which requires drug distribu- feiting and diversion. The FDA intends on the Task Force's recent findings intors to provide documentation of the to announce that the availability of a numerous contacts with stakehold-chain of custody of drug products—the draft compliance policy guide for pub- ers, including a February 2006 publicso-called "pedigree"—throughout the lie comment describing this enforce- workshop, a request for public com-distribution system. ment approach will be available in the ment, and monitoring of the latest

The FDA had p laced cer ta in regu- Federa l Regis ter. technolog ica l developments ,latory provisions on hold because of By providing guidance on the types This latest report is the third in aconcerns raised at the time about the of drugs that are currently of greatest series of documents exploring ways toimpact on small wholesalers. Most concern to the FDA, the agency intends ensure the safety of the U.S. drug sup-recently, in early 2004, the FDA delayed to give wholesale distributors a better ply. The first report, issued in 2004,the effective date of certain regulatory idea on where and how to focus their outlined the framework for protect-provisions regarding pedigrees to allow initial energies to come into complete ing the public from counterfeit medi-the industry time to adopt electronic compliance with the regulations for all cines. The second report, released lasttechnology for tracking drugs through the prescription drugs they distribute, year, assessed the progress towardthe supply chain. Under appropriate circumstances, the implementing the 2004 recommen-

On the basis of information from agency may initiate regulatory action, dations. ■drug supply stakeholders, the FDA had including criminal prosecution, forexpected this technology to be in wide- pedigree violations that do not meet For More Informationspread use in the drug supply chain the factors listed in the guidance. FDA Task Force Reportsby 2007. But it now appears that these The Task Force report also under- www.fda.govjcounterfeitexpectations will not be met. lines the agency's belief that wide-

Furthermore, concerns raised in the spread use of electronic pedigrees (e-past regarding the impact on small pedigrees) using electronic track andwholesalers have not been repeated. In trace technology, including radio fre-

CurbingC o u n t e r f e i tDrugs

DA Consumer / September-October 2006 / 1

I nfluenza :Vaccination Still theBest ProtectionBy Linda Bren

NO one could say that the threat of bird influenza—along with talk of widespread illness, quarantines,and school and business closings—isn't alarming.

The risk is real. Health officials are not downplaying it, andthe nation is preparing for it aggressively at federal, state,and local levels.

C e n t e r s f o r D i s e a s e C o n t r o l a n d P r e v e n t i o n

A photograph of influenza A virus taken through an electron microscope.

Bird (avian) influenza is caused byinfluenza viruses that occur naturallyi n w i l d b i r d s . T h e a v i a n i n fl u e n z acurrently of concern, the H5N1 subtype, can be transmitted from bird tobird and, less frequently, from bird tohuman. The fear is that the virus willmutate into one that will spread easily from person to person, causing apandemic—a worldwide outbreak ofs e r i o u s i l l n e s s .

But people should not let the fearo f a v i a n i n fl u e n z a d i s t r a c t t h e m f r o m

paying attention to the more predictable seasonal influenza, experts say.

"Clearly there's been a growing concern among Americans about a possible future avian influenza pandemic,"says William Schaffner, M.D., professor and chairman of the Departmentof Preventive Medicine at Vanderbi l t

University School of Medicine in Nashville, Tenn. "There is no evidence ofavian influenza [H5N1] among avians in this entire hemisphere let aloneamong people. But there will be influenza annually—real traditional, seas o n a l i n fl u e n z a . "

Seasonal influenza is among America's most lethal killers, according tothe Centers for Disease Control andPrevention (CDC), because the virusinfects so many people—5 percent to20 percent of the U.S. population everyyear. Most people who get this contagious respiratory illness caused by theinfluenza virus recover in a week ortwo without complications. But eachyear, more than 200,000 people havecomplications severe enough to sendthem to the hospital. And another36,000 die each year from seasonalinf luenza—more than 250 t imes thenumber who have d ied in the last three

years from avian influenza, reported to


be 133 by the World Health Organization (WHO) as of July 20, 2006.

Ninety percent of the deaths fromseasonal influenza occur in those ages65 and older, but the highest ratesof infection occur in children. Andhealthy children younger than 2 yearsare as likely to land in the hospitalbecause of influenza as those over 65.

"Vaccination remains the single mosteffective preventive measure availableagainst influenza, and can preventmany illnesses and deaths," says JesseGoodman, M.D., director of the Foodand Drug Administration's Center forBiologies Evaluation and Research(CBER). Yet each year, millions ofAmericans choose to take a chance and

forgo influenza vaccination.Public health officials urge those eli

gible for vaccination to receive it andremind people that although influenzavaccination begins in September orOctober each year, vaccine continues tobe available in November, December,and later, and immunization duringt h o s e m o n t h s i s s t i l l b e n e fi c i a l .

The CBER regulates vaccines for usein the United States and is responsible for their safety and effectiveness."Ensuring an adequate, safe, and effective supply of influenza vaccine eachyear is one of FDA's highest priorities,"says Goodman.

W h o S h o u l d G e t V a c c i n a t e d ?Va c c i n e i s a v a i l a b l e t h i s s e a s o n t o

anyone who wants to reduce his or herchances of getting influenza, with a fewexceptions, but the CDC strongly recommends it for certain people—thoseat high risk for serious influenza complications and those who live with orcare for people at high risk, such ashealth care workers, nursing home

staff, and home caregivers. Croups athigh risk are identified in the springof each year by the CDG's AdvisoryCommittee on Immunization Practices(ACIP). The CDC formally issues orreiterates the AClP's recommendationsin the summer. Influenza vaccine is notrecommended for certain people, suchas those allergic to eggs.

To protect more children at risk forserious influenza-related complications, the ACIP recommended in 2006that children 6 months to 59 monthsof age be vaccinated. This recommendation expands the previous one tovaccinate from ages 6 months to 23months. Children younger than 9 yearsreceiving the vaccine for the first timen e e d a b o o s t e r d o s e o n e m o n t h a f t e r

t h e i n i t i a l d o s e .S i n c e n o i n fl u e n z a v a c c i n e i s

approved for children younger than6 months of age, families should usea strategy known as "cocooning," saysSchaffner. "They should provide acocoon, or zone of protection, aroundthat very vulnerable young child byvaccinating all the other people in thefamily, including grandma and granddad who come in for visits, and out-of-home caregivers."

H o w W e l l D o e s I n fl u e n z aV a c c i n e W o r k ?

Influenza vaccine works by stimulating our immune system to makeantibodies—proteins that specificallyrecognize and target influenza virusesand help eliminate them from the bodyw h e n w e e n c o u n t e r t h e m . I n f e c t i o n -

fighting antibodies develop about twow e e k s a f t e r v a c c i n a t i o n .

S t u d i e s h a v e s h o w n t h a t i n fl u e n z avaccine is 70 percent to 90 percenteffective in healthy adults younger

Centers for Disease Control and Prevention

A vial containing the Influenza VirusVaccine, Fluzone, distributed by AventisPas teu r, USA.

than 65. In older people, children,and those with chronic i l lnesses, thevaccine may not necessarily preventinfluenza, but it can reduce the severityof the symptoms and the risk of complications if they do get sick.

Vaccination in people older than 65reduces the likelihood of hospitalization for influenza-related complications by 30 percent to 70 percent. Andfor those living in nursing homes orother long-term care facilities, the vaccine is up to 80 percent effective in preventing death from influenza.

Two Types of Influenza VaccineThe FDA has licensed two types of

influenza vacc ine f o r use i n t he Un i t edS t a t e s : t h e " s h o t " a n d t h e i n h a l e d v a cc i n e .

The sho t con ta ins i nac t i va ted , o rkilled, viruses and is given with a need l e i n t h e a r m . T h e i n h a l e d v a c c i n econtains live viruses that are weakened,or attenuated, and is administered intothe nose with a sprayer. The influenzashot can be given to those 6 monthsof age and older, including healthypeople and those with medical conditions. The inhaled vaccine is approvedonly for healthy people between theages of 5 years and 49 years, excludingp r e g n a n t w o m e n .


Production Schedule for Influenza Vaccine

A r t v i l l e

C e n t e r s f o r D i s e a s e C o n t r o l a n d P r e v e n t i o n

Y e a r - R o u n d

Officials track influenza worldwide to help predict severity andtiming for the upcoming season in the United States.

FebruaryThe ACIP/CDC issues early recommendations for vaccination for theupcoming season.

The FDA advisory committee, in collaboration with the WFIO,selects three strains to be included in vaccine.

M a r c h - A p r i lLicensed manufacturers receive reference viruses from the WFIO

collaborating centers, which include the FDA and the CDC.Manufacturers generate seed viruses tested by the FDA to ensurethat they are the same as the recommended strains. Viruses areinjected into fertilized chicken eggs.

A p r i l - J u n eManufacturers harvest and purify the virus from the eggs.

J u n e

The ACIP/CDC meets and reiterates/updates recommendations.

M a y - J u l yThe FDA provides antiserum to manufacturers to test each strain'spotency.

J u l yManufacturers blend three strains into one vaccine and ship samplevaccines to the FDA for release.

A u g u s tManufacturers fill vials with vaccine and prepare to ship them.

S e p t e m b e r - N o v e m b e rManufacturers ship vaccine to health care professionals forimmunization; vaccine manufacturing continues.

O c t o b e r - N o v e m b e rVaccination begins.

D e c e m b e r - M a r c h

Influenza disease activity continues; immunization is still beneficial.

ACIP - Advisory Committee on Immunization PracticesCDC - Centers fo r D isease Cont ro l and Prevent ionFDA - Food and Drug AdministrationWHO - World HealtFi Organization


The most common side effect of theinfluenza shot is soreness where theshot is given. Some people may get amild fever, body aches, and fatigue fora few days, but you can't get influenzafrom the influenza shot, says KarenMidthun, M.D., the CBER's deputyd i rec to r f o r med i c i ne . "No vacc ineis 100 percent effective. So you mayget the flu soon after you received thevaccine, before it could be expected toprotect you. It does not mean the shotgave you the flu."

N e i t h e r d o e s t h e i n h a l e d v a c c i n ecause influenza in healthy people, theonly group for which it's approved."Some people may get a mild runnynose," says Goodman. Other mild sideeffects are nasal congestion, headache,sore throat, cough, and muscle aches.

A Ye a r - R o u n d P r o c e s s

Preparing for the influenza seasoneach year is a time-critical, highlyo r c h e s t r a t e d , c o l l a b o r a t i v e e f f o r tbetween the FDA, CDC, National Institutes of Health (NIH), WHO, vaccinemanufacturers, and the health community. The year-round process requiresongoing worldwide influenza diseasesurveillance, development of recommendat ions for immunizat ion, se lection of virus strains, preparation ofa n t i s e r u m u s e d f o r s t a n d a r d i z a t i o nof new vaccine, and manufacture andd i s t r i b u t i o n o f n e w v a c c i n e .

One of the biggest challenges in theprocess is to produce a new vaccineevery year, says Goodman. "Becausethe virus mutates, each year's vaccinemay be different from the precedingyear."

"The manufacturing demands aretremendous," adds Goodman. "There'sno other instance where a new vaccineis made every year, and actually threenew vaccine components are madebecause there are three strains withino u r a n n u a l fl u v a c c i n e . "

Each year, the vaccine formulationdepends on the strains that are predicted to be circulating that season. Thecloser the match between the circulat

ing strains and the strains that makeup the vaccine, the better protectionthe vacc ine o f fe rs .

The process begins in late Januaryor early February when an FDA advi

sory committee meets to recommendwhich three strains of the virus shouldbe included in the vaccine, based ondata from WHO laboratories in morethan 80 countries. The FDA and theG D G c o l l a b o r a t e w i t h t h e W H O o nstrain selection, and the FDA makesthe final decision on which strains willbe included in the vaccine for the U.S.population. This season's formulationfor the U.S. vaccine is identical to thatrecommended by the WHO, and itincludes one virus from last year's vacc i n e a n d t w o n e w v i r u s e s .

Once the strains are selected, theFDA, GDG or other WHO collaborating centers can produce reference influ

enza viruses that are adapted to highgrowth in eggs. The reference influenzaviruses are provided to the licensedvaccine manufacturers to generate the"seed virus" for further manufacturinginfluenza vaccine. Following a rigorousreview of safety and effectiveness dataon manufacturers' vaccine products,the FDA has licensed four manufacturers to produce influenza vaccine for the2 0 0 6 - 2 0 0 7 s e a s o n .

Using an automated system, manufacturers inject the seed viruses intofertilized chicken eggs, which containa n u t r i e n t i n w h i c h t h e v i r u s m u l t i

plies. "The high-growth virus generallygrows well in fertilized hens' eggs,"

Influenza DrugsGetting an annual influenza vaccination continues to be the first line

of defense against seasonal influenza. But antiviral drugs—started withinthe first two days of experiencing influenza symptoms—can shorten thet i m e i n fl u e n z a l a s t s .

The FDA has approved four antiviral prescription drugs to treat influenza: Tamiflu (oseltamivir), Relenza (zanamivir), Symmetrel and generics(amantadine), and Flumadine and generics (rimantadine). These drugsare in two classes, the adamantanes (amantadine and rimantadine) andneuraminidase inhibitors (oseltamivir and zanamivir).

All four of these drugs also are approved to prevent influenza, but theyare not substitutes for influenza vaccine. The Genters for Disease Gontroland Prevention (GDG) recommends that the drugs be used in specific circumstances, for example, in combination with the vaccine to help controlinfluenza outbreaks in institutions such as nursing homes where people athigh risk for complications from influenza are in close contact with eachother. The GDG says, however, that people who receive inhaled vaccinethat contains live viruses should not use antiviral drugs for at least twoweeks after vaccination and should not get vaccinated within two days ofstopping the use of antiviral drugs.

The drugs may be prescribed by a doctor to prevent influenza in placeof vaccine in certain people, such as those who are allergic to eggs, themedium used to grow the virus for the vaccine.

Influenza viruses can rapidly develop resistance to certain drugs. Becauseof recent evidence that many circulating influenza viruses are resistant toamantadine and rimantadine, the CDC has recommended that these drugsnot be used for influenza in the United States at this time.

The emergence of resistant strains of influenza was a catalyst for a regulation, which became effective June 20, 2006, prohibiting the use in chickens, turkeys, and ducks of the adamantane and neuraminidase inhibitorclasses of human antiviral drugs for influenza, including all four approveddrugs listed above. Although the FDA has not approved any veterinarydrugs to treat or prevent influenza in animals, veterinarians can legallyprescribe human drugs for use in animals under certain conditions, apractice known as extralabel use. The FDA may prohibit such extralabeluse in animals, however, if it presents a risk to public health. ■


Getty Images

Hunein "John" Maassab, a professor of epidemiology at the University of Michigan,developed a nasal-introduced influenza vaccine called FluMist through theUniversity of Michigan.

says Norman Baylor, Ph.D., director ofthe CBER's O ffice o fVacc ines Researchand Review. "Fertilized hens' eggs havebeen used safely and successfully toproduce influenza vaccine since thela te 1940s . "

The manufacturer harvests and purifies the virus from the egg and applieschemical treatments to kill (inactivate)t h e v i r u s s o t h a t i t c a n n o t t r a n s m i ti n f e c t i o n . T h e s e t r e a t m e n t s a r e d o n efor each of the three strains (monovalents) , which are tested and retested byb o t h t h e m a n u f a c t u r e r a n d t h e C B E R

before being blended into the three-virus strain (trivalent) vaccine.

The CBER produces and providesm a n u f a c t u r e r s w i t h a n t i s e r u m . T h e

antiserum is collected from sheepthat have been injected with a purifiedinfluenza protein, causing the sheept o m a k e a n t i b o d i e s t o t h a t i n fl u e n z a

protein. The antiserum then is used totest vaccine potency for each influenzastrain. Vaccine potency is determinedby the manufacturer for each monova-lentvaccine pool. "This is a critical stepin the process, because you need tocheck the potency of each of the monovalents prior to blending," says Baylor, so that manufacturers can blend

the right amount of each monovalenti n t o t h e fi n a l t r i v a l e n t v a c c i n e .

Manufacturers ship sample vialsof vaccine from each lot, along withtheir test results, to the CBER for "lotr e l e a s e . " T h e C B E R r e v i e w s t h e t e s tresults as well as performs its own teststo ensure the accuracy of the manufacturers' tests and the vaccine's safety andeffectiveness before releasing each lotf o r d i s t r i b u t i o n .

Some lots of vaccine may be releasedas early as July, but manufacturing usually continues until October or laterin order to produce and test the largevolume of vaccine required for the U.S.population.

It takes about six months to completeinfluenza vaccine production—fromegg to vial—each season. Throughoutthe process, the FDA discusses technical and manufacturing issues with thecompanies and inspects each company's facility and manufacturing processes while it is making vaccine.

"Each year, FDA begins workingw i t h m a n u f a c t u r e r s a t t h e e a r l i e s t

stages of influenza vaccine development," says Goodman, "and we continue to assist them throughout theproduction phase."

Vaccine Supply and ShortagesSelecting the influenza virus strains

each year, preparing the vaccine, andmanufacturing and distributing millions of doses all must be preciselyt i m e d t o m a k e t h e v a c c i n e a v a i l a b l efor the influenza season. Any problems encountered during the processmay cause delays or shortages, saysGoodman. In addi t ion, because thenumber of companies that make influe n z a v a c c i n e f o r t h e U n i t e d S t a t e s i s

small, a production problem with anycompany can substantially affect theoverall supply.

Manufacturers have projected making about 100 million doses of influe n z a v a c c i n e f o r t h e 2 0 0 6 - 2 0 0 7 s e a

son, but these projections could changeas manufacturing continues. The projected supply is 16 percent more thant h e 2 0 0 5 - 2 0 0 6 s e a s o n ' s 8 6 m i l l i o n

doses and 40 percent more than the2 0 0 4 - 2 0 0 5 s e a s o n ' s 6 1 m i l l i o n d o s e s .Demand has usually been around 70m i l l i o n t o 7 5 m i l l i o n d o s e s .

"Influenza vaccine supply and distribution are very closely tied to theissue of demand," says public healthresearcher Ghristine Layton, Ph.D.,M.P.H., of RTI Internat ional , a nonprofit firm in Research Triangle Park,N.C. "Vaccine manufacturers produceas much vaccine as they anticipate theycan sell. If they're unable to sell the vaccine, they take a loss."

A loss may mean they'll make lessvaccine next season, says Layton, orthey may want to get out of the influenza vaccine business altogether."From a public health standpoint, wewant to make sure that folks get flushots so as much vaccine that is produced i s used . "

Government agencies monitor thevaccine market, but do not control it.Distributing and administering influenza vaccine is mostly a private sectorenterprise. The CDC and state and localhealth departments work to influencedistribution through collaborationsa n d r e c o m m e n d a t i o n s s o t h a t v a c c i n ereaches the people most at risk, including older people, health care workers,nursing home residents, young children, and expectant mothers.

Vaccine distribution is a complexprocess, says Layton, involving manu-


facturers, wholesalers, distributors,purchasers, and providers. The providers may be private immunizers, suchas doctors and nurses in private practice; community immunizers, such asvisiting nurse associations; or massimmunizers, such as companies thatcome into a workplace or a retail establ i s h m e n t .

Some manufacturers sell directly toproviders, others work exclusively withwholesalers, and some use both methods of distribution. In past seasons, saysLayton, "where you ordered your vaccine from had a significant impact onhow much vaccine you had." Since thereis no coordinated system that manufacturers and distributors use to delivervaccines, some health care providersreceive their vaccine before others.

"Oftentimes, people will say, 'myown doctor doesn't have vaccine butthe Costco has vaccine, or the Safewayhas vaccine,'" says Layton, but thatdoesn't mean retailers get preferential treatment. "The retailers have not

bought the vaccine. They have hired, asa customer service, a mass immunizerand have offered them space to do anonsi te c l in ic . " And the mass immunizer and the doctor's office may havepurchased vaccine through differentd i s t r i b u t i o n c h a n n e l s .

Extending the ImmunizationS e a s o n

Sometimes, vaccine is in short supply early in the season, but there isleftover vaccine at season's end. Howmuch vaccine is produced and distributed plays a role, says Layton, but sodoes timing. "The peak demand forflu vaccine is in October and November, when only about 50 percent of thevaccine has been del ivered. But i t 's notuntil January, generally speaking, thatall the vaccine has been available to

providers."And it's usually not until January or

la te r tha t the influenza d isease season

peaks in the United States, according tothe CDC. The FDA and the CDC support extending vaccination throughoutthe influenza season, into January andFebruary.

The American Medical Associat ion(AMA) also strongly supports an extens i o n o f t h e i n fl u e n z a i m m u n i z a t i o n

season, says Ardis Hoven, M.D., anAMA spokeswoman and medical director of the University of Kentucky'sBluegrass Care Clinic in Lexington."We know that the manufacturerscannot del iver al l 100 mi l l ion dosesof vaccine early in the season—it's gotto be staggered. For certain high-priority populations, receiving vaccinationearly in the season is obviously preferable. But the benefits of flu vaccineremain even when vaccinating throughJanuary and beyond, particularly if fluhasn't even hit the community yet."

Getting people vaccinated later inthe season is challenging, says Schaff-ner, adding that there is a culture, ormindset, that needs to be changed inboth vaccine providers and vaccinerecipients. "From the point of view ofproviders, there's the sense that influ

enza immunization should be done byThanksgiving."

Layton concurs that the holidaysaffect vaccine providers, such as storestha t o f fe r influenza vacc ine c l in i cs ."Retailers don't want to give up floorspace during the holidays—they needthat floor space for selling seasonalmerchandise. They want to finish upshots around the end of October or

beginning of November.""I think that our patients, too, get

preoccupied with the holidays," saysSchaffner. "We need to persuade themthat it's not too late to get vaccinatedwell into December, January, and eveninto February."

New Vacc ines , Fas te r P roduc t ionT h e c u r r e n t m e t h o d o f i n fl u e n z a

vaccine production uses millions ofchicken eggs each year to grow thet h r e e d i f f e r e n t s t r a i n s o f i n fl u e n z aviruses—about 300 million eggs willbe needed for this season's projected1 0 0 m i l l i o n d o s e s .

The process is complex and time-consuming, says Goodman. "It presents anenormous challenge for manufacturersand creates uncertainty for the vaccinesupply."

Scientists and public health expertsare looking for ways to boost the production of influenza vaccine and makeit available more quickly to more people. And researchers are looking atnew technologies that could be used toproduce vaccine, not just for seasonalinfluenza, but for a pandemic.

"With adequate supply and widespread immunization, we will be morelikely to meet the challenge of annualinfluenza epidemics and future pandemics," says Goodman.

One of the technologies researchersare using is cell culture production,which allows a virus to grow and multiply in living animal cells instead ofeggs. Cell-based vaccines could helpmeet surge capacity—making a lot ofvaccine in a short time period—in theevent of a shortage or a pandemic.

Making the vaccine initially in cellculture wouldn't save much time overthe egg-based process, says GeorgeC u r l i n , M . D . , M . P. H . , a n i n f e c t i o u s

Good Hea l t h Hab i t sThe Centers for Disease Control and Prevention recommends practicing

good health habits to help prevent getting influenza:• Avoid close contact. Keep your distance from people who are sick.• Stay home when you are sick. If possible, stay home from work, school,

and errands when you are sick. You will help prevent others from catchingyour illness.

• Cover your mouth and nose. Use a tissue when coughing or sneezing.It may prevent those around you from getting sick.

• Clean your hands. Wash your hands frequently with warm, soapy waterfor about 15 seconds. It will help protect you from germs.

• Avoid touching your eyes, nose, or mouth. Germs are spread when aperson touches something that is contaminated with germs and thentouches his or her eyes, nose, or mouth. ■


Influenza Causes Significant Numbersof HospitalizationsYoung children, especially those with certain underlying medicalconditions, have high rates of influenza-related hospitalizations.

r oNc( U3

( U3

• a\ / \co

mN

"5'5 .oX

C LoOJQ .

ooo

< DO

With high-risk conditions

Without high-risk conditions

O JQ .

less than 1

Age in Years

Centers for Disease Control and Prevention and the National Foundation for Infectious Diseases

Who Shou ld Get Vacc ina ted?The Centers for Disease Control and Prevention recommends influenza

vaccination each year for the following groups of people:

• All children 6 months to 59 months of age—a new recommendationf o r t h i s i n fl u e n z a s e a s o n

• Women who will be pregnant during the influenza season• People ages 50 years and older• Children and teen-agers (ages 6 months to 18 years) who must take

aspirin regularly and therefore might be at risk for developing Reyesyndrome if they get influenza

• Adults and children ages 6 months and older with chronic heart or lungconditions, including asthma

• Adults and children who have required hospitalization or regulardoctor visits during the past year because of chronic metabolic diseases(including diabetes), kidney disease, hemoglobin abnormalities, orweakened immune system (for example, caused by medications or HIVinfection)

• People with any condition that makes it hard to breathe or swallow,such as brain injury or disease, spinal cord injuries, seizure disorders,o r o t h e r n e r v e o r m u s c l e d i s o r d e r s

• Residents of nursing homes and other facilities that provide care forpeople with chronic medical conditions

• Healthy household contacts and caregivers of children up to 5 years oldand people at high risk for severe complications from influenza

• H e a l t h c a r e w o r k e r s . ■

diseases researcher and adviser onvaccine clinical trials at the NationalInstitute of Allergy and Infectious Diseases. "We'll still have to go throughthe annual process every year to makea match with the circulating virus. Butshould we need to ramp up production very, very quickly, you can use celltechnology to do that faster than youcan increase the availability of eggs."

With cell culture production, cellscan be frozen and stored, and thenthawed out and used to produce morevaccine as needed—a speedier processthan acquiring millions more fertilizedeggs. Like the current method of influenza vaccine production, the safety ofvaccines produced in cell culture wouldbe thoroughly evaluated by the FDA.

In May 2006, Health and Human Services Secretary Mike Leavitt announcedthe department's investment of morethan $1 bil l ion in contracts with fivecompanies to develop influenza vaccine made from cell culture. "Our current capacity of egg-based influenzavaccine production is not sufficientto meet increased demands during anemergency," said Leavitt. "Acceleratingthe development of this vaccine technology and creating domestic capacity are critical to our preparednesse f f o r t s . "

Researchers also are looking at recombinant vaccines, made by genetic engineering, for influenza prevention. Thegene from a specific influenza proteinis isolated f rom the influenza vi rus,cloned, and grown in yeast or othercells to create large amounts of the protein. The protein produced is purifieda n d t h e n u s e d t o m a k e v a c c i n e . W h e nthe vaccine is injected into a person,the body's immune response to therecombinant protein protects againstinfection by the naturally occurringv i r u s .

C e l l c u l t u r e a n d r e c o m b i n a n t m e t hods hold promise for developing newinfluenza vaccines, but researchers alsoare experimenting with substancest h a t e n h a n c e v a c c i n e e f f e c t i v e n e s s

(adjuvants) to make current vaccinesmore potent. "If you could double thepotency, the current technology couldmake twice as many doses," says Cur-lin, "which would make 50 percent ofthe doses available sooner." NIH-sup-


ported studies are under way usingadjuvants as a "dose-sparing" technology.

Another area of research is a universalv a c c i n e . T h i s o n e - s h o t - fi t s - a l l v a c c i n ewould protect people for years againstall strains of influenza anywhere in theworld. "A universal vaccine would not

require an annual change in the vaccine," says Curlin. "We wouldn't haveto go through this annual complex,highly choreographed process whichsucceeds, but is a race against timeevery year." Although universal vaccineresearch has been going on for decades,says Curlin, "nothing seems like it'savailable right around the corner, butthere are clinical trials starting."

The FDA has worked to streamlinethe vaccine approval and licensing process to encourage new vaccine developm e n t a n d t o m a k e v a c c i n e s a v a i l a b l efor use sooner. In March 2006, theagency published recommendations,in the form of two draft guidelines, toaid manufacturers in developing vaccines for both seasonal and pandemicinfluenza. The guidelines give specificapproaches that vaccine developers canfollow to show the safety and effectiveness of new vaccines, and they provideflexible, regulatory pathways for getting vaccines on the market.

One of these pathways is the accelerated approval process, which canreduce the development time for anew vaccine. For an application thatdoes not use the accelerated approvalpathway, a company must show thata vaccine actually prevents influenza,which requires waiting to see whetherpeople in studies get sick or not. Foraccelerated approval, if the manufact u r e r d e m o n s t r a t e s t h a t w i t h i n w e e k safter vaccination, adequate levels ofprotective antibodies are made in theblood that the FDA believes may prevent influenza, then this approachmay be acceptable. If the acceleratedapproval approach is used, furtherstudies are required after approval tomake sure that the vaccine actuallyprevents influenza.

The accelerated approval pathwaywas critical in allowing the rapidapproval in 2005 of Fluarix, a newi n fl u e n z a v a c c i n e a n d t h e fi r s t v a c c i n eof any kind approved using the FDA's

Where to Get Influenza Vacc ineFor individuals who are searching for a place to get an influenza

vaccination, the Centers for Disease Control and Prevention (CDC)suggests the following:

• Contact your personal health care provider.• Check the American Lung Association's XocdXoi dXwwiv.flucliniclocator.org

for influenza clinics in your area.• Call your local public health clinic or state health department

immunization program. Or call the CDC at (800) CDC-INFO (232-4636).

• Check newspapers, radio stations, or other public information sourcesfor specific clinics in your community.

• Check with your county medical society. ■

accelerated approval process.Baylor says that because these guide

l i n e s w i l l a s s i s t m a n u f a c t u r e r s i n t h e

development and evaluation of newvaccines for seasonal and pandemicinfluenza, the direction that they provide to new manufacturers , in turn,helps address the increased demand forinfluenza vaccine. Having additionalmanufacturers will enhance the capacity to produce more doses of influenzavaccine and contribute to the nation's

pandemic preparedness. "Manufacturers who are already licensed for a seasonal vaccine would require limitedclinical data for a new pandemic vaccine license, since the pandemic influe n z a v a c c i n e w o u l d b e m a n u f a c t u r e d

by the same process as the seasonalvaccine," Baylor says.

In recognition of the different technologies available to researchers, theguidelines apply to specific approachesfor vaccine development using cell culture, recombinant manufacturing, andnewer technologies.

The FDA is committed to helpingcompanies develop safe and effectivevacc ines fo r the seasona l influenzavirus as well as assisting them with thedevelopment of a pandemic influenzavaccine when one becomes necessary.The release of the guidelines is just partof the cumulative effort that the FDAis undertaking to help in the development of vaccines. Another example includes correspondence with themajor manufacturers of influenza vacc i n e i n t h e w o r l d t o s t i m u l a t e i n t e r e s tin producing vaccine for the U.S. mar

ket. This outreach resulted in one additional vaccine product approval for the2005-2006 season, and the possibilityfor others in future influenza seasons.The FDA is also undertaking efforts tofacilitate development of influenza vaccines using new technologies, including cell-based, and other novel typessuch as DNA and synthetic peptide. Toaccomplish this goal, the CBER is usingvarious approaches to reach a broadaudience, such as convening an advisory committee meeting to discuss theuse of novel cell substrates for makinginfluenza vaccine, and frequent interactions with vaccine manufacturers toprovide both scientific and regulatoryguidance. In addition, the CBER isparticipating in and leading meetingswith industry, regulatory authorities ofother nations, and stakeholders con

cerning the development of influenza

F o r M o r e I n f o r m a t i o n

www.fda.gov/oc/opacom/hottopics/flu.h t m l

www.cdc.gov/flu/

www.pandemicflu.gov


Pain Drugs for Dogs:Be an InformedP e t O w n e rBy Linda Bren

A decade ago, few drugs were availableto treat pets in pain at home. Pupswere spayed or neutered at the animal

hospital, stitched up, and sent home withoutpain medication. And dogs with painful arthritislimped along without drugs that were safe andeffective for long-term use.

Today, a new generation of nonsteroidal anti-inflammatorydrugs (NSAIDs) is bringing relief to millions of dogs with jointproblems or with pain after surgery.

"NSAIDs are extremely effective for controlling pain andinflammation in dogs," says Stephen F. Sundlof, D.V.M., Ph.D.,director of the Food and Drug Administration's Center for Veterinary Medicine (GYM). "These are very valuable drugs thathelp many pets live to a ripe old age."

But like any drugs, NSAIDs carry a risk of side effects, oradverse reactions. Most adverse reactions are mild, but some

may be serious, especially if the drugs are not used accordingto labeled directions. Some reactions result in permanent damage or even death.

"It's important for pet owners to be aware of the risks andbenefits of all drugs, including NSAIDs, so that they can makeinformed decisions about their pets' health care," says Sundlof. "Owners who give their dog NSAIDs need to know theside effects to watch for that indicate their pet needs medicala t t e n t i o n . "

O.B., an Irish Wolfhound, owned by Lynne Heslip of Howell,Mich., was given NSAIDs for three years to successfully treatpainful hip dysplasia.


Drugs used to control pain should be given only whennecessary, and in the smallest dose that is effective.

The most common side effects fromNSAIDs include vomiting, loss of appetite, depression, lethargy, and diarrhea.Serious side effects include gastrointestinal bleeding, ulcers, perforations,kidney damage, and liver problems.

"The s ide e f fec ts o f NSAIDs a re

very well known and very well documented," says Michele Sharkey, D.V.M.,in the CVM's Office of New AnimalDrug Evaluation. But this information is not always getting to the petowner, she says. "If the pet owner canrecognize a possible reaction, stop themedication, and get veterinary help, itcould mean the difference between agood outcome and a disaster."

Safety and EffectivenessThe CVM, which regulates drugs for

use in animals, has approved someNSAIDs for use in dogs with pain fromdegenerative joint disease (osteoarthritis) or with pain after surgery. Theseinclude Etogesic (etodolac), Rima-dyl (carprofen), Metacam (meloxi-

cam), Zubrin (tepoxalin), Deramaxx(deracoxib), Previcox (firocoxib), andNovox (generic carprofen).

NSAIDs help to control signs ofar thr i t is , inc lud ing inflammat ion,swelling, stiffness, and joint pain.Inflammation—the body's response toirritation or injury—is characterized byredness, warmth, swelling, and pain.NSAIDs work by blocking the production of prostaglandins, the body chemi c a l s t h a t c a u s e i n fl a m m a t i o n .

The FDA considers approved NSAIDst o b e s a f e a n d e f f e c t i v e w h e n u s e d

according to the label and when dogo w n e r s a r e i n f o r m e d a b o u t c o m m o nN S A I D a d v e r s e r e a c t i o n s .

And veterinarians are becomingincreasingly aware of the advantages ofrecognizing and controlling pain, saysCharles Lemme, D.V.M., a member of

ciation (AVMA), Clinical PractitionersAdvisory Committee. "We recognizethat pets are healing better and fasterwith pain control."

Medicate Under Veterinary SupervisionThe FDA has approved some nonsteroidal anti-inflammatory drugs

(NSAIDs) for use in dogs. In the United States, there are no oral NSAIDsapproved for use in cats. Veterinarians can, however, legally prescribehuman drugs to animals unless it presents a risk to the public health.This type of use is known as extralabel, or off-label, for uses not listedon the label. Extralabel use can also mean prescribing a drug to adifferent species, for a different condition, or in a different dosage thanthat for which the drug was approved. For example, a veterinarian mayprescribe a lower dose of an NSAID drug approved for dogs to a cat withan inflamed joint.

But pet owners should not give their own drugs to pets or otherwisemedicate their animals without veterinary supervision, says MicheleSharkey, D.V.M., in the FDA's Center for Veterinary Medicine.

Different species metabolize drugs differently, she says. "You takeaspirin or Tylenol on any given day for a headache and not think twiceabout it, but dogs are more sensitive to aspirin than humans, andone Tylenol can kill a cat. Pet owners should always work with theirv e t e r i n a r i a n s t o m a k e m e d i c a t i o n d e c i s i o n s . " ■

Lemme says that the emphasis onpain management may be partlybecause of the availability of the newerNSAIDs. "The NSAIDs we have available now are a lot safer than what we'vehad before and we're seeing far fewerside effects than before."

Before the newer generation ofNSAIDs came along, "people wereusing NSAIDs such as aspirin in anattempt to mitigate arthritic pain," saysMichael Andrews, D.VM., president ofthe American Animal Hospital Association (AAHA). "We saw the consequence of their use," adds Andrews,who recalls seeing a client who gave herdog aspirin for six weeks, two times aday. "The dog had a bleeding nose thatwouldn't stop."

"NSAIDs are used in many, manydogs and the frequency of problems isquite low," says Andrews. "The duration of use makes a difference in safetyIf used for a day or two, the risks oftena r e m u c h l o w e r t h a n w h e n u s e d o v e r

long periods of time for a chronica r t h r i t i c c o n d i t i o n . "

Drugs used to control pain shouldbe given only when necessary, andin the smallest dose that is effective,says Sharkey. "Arthritis waxes andwanes. Some animals get worse in coldweather. If the dog seems to improve tothe point of not needing the drug, theowner should discuss continued use ofthe NSAID with a veterinarian."

An owner should never give anNSAID to a pet, or increase the doseor frequency of a drug, without theveterinarian's instructions, adds Sharkey. "Just like different people responddifferently to a drug, the way eachdog responds to an NSAID varies."Because of this individual response, noo n e N S A I D i s c o n s i d e r e d m o r e e f f e ctive than another, and because everyNSAID can cause adverse reactions,n o n e i s c o n s i d e r e d s a f e r t h a n o t h e r s .

If a pet is prescribed an NSAID, theCVM recommends that pet owners takethe following steps to make sure they

22 / FDA Consumer / Sep -October 2006

P r e v i c o x(firocoxib)

Information for Dog Owners aboutPREVICOX™ (firocoxib) Chewable Tablets

PREVICOX^" Chewable Tablets are for control of osteoarthritis pain and inflammation in your dog.

This summary conlains important information atwut PREViCOX. You should read this information before you start giving your dog PREVICOXtablets and review it each time your prescription is refilied. This sheet is provided only as a summary and does not tate the place of instmctionsfrom your veterinarian. Talk to your veterinarian if you do not understand any of this information or you want to know more about PREViCOX.

W h a t i s P R E V I C O X ?PREVICOX is a veterinary prescription non-steroidal anti-inflammatory drug ff4SAID) used to control pain and inflammation due to osteoarthritis indogs. Osteoarthritis is a painful condilion caused by "wear and tear" of cartilage and other parts of the joints that may result in the followingchanges or signs in your dog:

• Umping or lameness.• Decreased activity or exercise (reluctance to stand, dimb stairs, jump or run, or difficulty in performing these activities).• Stiffness or decreased movement of joints.

What kind of results can I expect when my dog is on PREVICOX for osteoarthritis ?VWiile PREViCOX is not a cure for osleoarthrilis, it can control Ihe pain and inflammation and improve your dog's mobility.

• Response varies from dog to dog. but improvement can be quite dramatic.• In most dogs, improvement can be seen within da) .• If PREVICOX is discontinued or not given as directed, your dog's pain and inflammation may return.

Which dogs should not take PREVICOX?Your dog should not be given PREWCOX If he/she:

• Has an allergic reaction to firocoxib, the active ingredient in PREVICOX.• Has had an allergic reaction (such as hives, facial swelling, or red or itchy sWn) to aspirin or other NSAIDs.• Is presently taking aspirin, other NSAIDs. or corticosteroids.• Is under seven pounds in body weight.

PREVICOX should only be given to dogs.People should not take PREViCOX. Keep PREViCOX and all medJcations out of the reach of children. Call your physician immediately if youaccidentally take PREVICOX.

What to tell/ask your veterinarian before giving PREVICOX.Talk to your veterinarian about:

• The signs of osteoarthritis you have observed in your dog, such as limping or stiffness.• The importance of weight control in the management of osteoarthritis.• What tests might be done befwe PREVICOX is prescribed.• How often your dog may need to be examined by your veterinarian.• The risks and benefits of using PREViCOX. Serious adverse reactions, including death, have been associated with PREVICOX administration

at doses above the recommended dose in puMJies less Uian seven mwiths of age.

Tell your veterinarian if your dog has ever had the following medical problems:• Any side effects from taking PREVICOX or other NSAIDs, such as aspirin.• Any digestive upset {vomiting and/or diantiea).• Any kidney disease.• Any liver disease.

Tell your veterinarian about:• Any other medical problems or allergies that your dog has now, or has had in the past• All medicines that you are giving or plan to give to your dog, including those you can get without a prescription and arry dietary supplements.

Tell your veterinarian if your dog;^fyouplanjj

M e r i a l L i m i t e d

The FDA has helped pharmaceutical companies develop ClientInformation Sheets for people whose dogs are prescribed NSAIDs.

are fully informed about the drug andcan make the best decision for theirpet's health.

Ask Quest ions and Tel l A l lAsk your veterinarian about the

benefi ts , r i sks , and s ide e f fec ts o fany medication, including NSAIDs."An informed dog owner is the bestdefense against serious side effectsfrom NSAIDs," says Sharkey. "Owners should not hesitate to ask questions and inquire about possible sideeffects or signs to watch for when treating a dog."

Teii your veterinarian your pet'ssymptoms and current medications,including prescriptions, over-the-coun-ter drugs, vitamins, herbal supplements, and flea control products. Giving NSAIDS and other medicationstogether could harm your pet. Aspirin,for instance, may he in a supplementyou're giving to your pet, says Sharkey,and should not he used in conjunctionw i t h a n N S A I D .

Ask f o r t he C l i en t I n fo rma t i onS h e e t

P e t o w n e r s s h o u l d r e c e i v e a " C l i e n tInformation Sheet" with every NSAIDpresc r ip t i on . C l i en t I n fo rma t ionSheets, a lso ca l led " In format ion forDog Owner Sheets," are user-friendlysummaries that explain the results toexpect from using the drug, what todiscuss with your veterinarian beforegiving the drug, possible side effects tolook for, and other important information. The FDA has helped the pharmaceutical companies who make NSAIDsfor dogs develop these sheets for theowners, and the companies providethem with each NSAID they ship.

Ask your veterinarian for the sheetif you do not receive one, and read theinformation carefully before givingthe medication to your dog. If yourveterinarian can't provide the ClientInformation Sheet, you can get one byprinting it from the CVM's Weh site orby calling the toil-free number of thedrug company.

Bernadette Dunham, D.V.M., Ph.D.,deputy director in the CVM's Office ofNew Animal Drug Evaluation, explainswhy some veterinarians may he unableto loca te the C l ien t In fo rmat ion Shee t .

"They often have the role of veterinarian and the role of pharmacist," shesays. Veterinary hospitals get shipments of drugs from the pharmaceutical companies or distributors. Thenthey may repackage the drug in theirhospitals' bottles, often in smallerquantities for distributing to clients.In the repackaging process, the Client Information Sheet, which is oftenprinted on the package insert for theveterinarian, may he tossed out inadvertently.

The FDA, the veterinary community,and the pharmaceutical companiesare working together to ensure thatNSAIDs are used safely and responsibly

and that owners are given the ClientI n f o r m a t i o n S h e e t s .

"The pharmaceutical companies aretrying to come up with creative ideasto make it easier for busy veterinarians," says Dunham. Many companiesare making the Consumer InformationSheet a tear-off sheet that can he easilyseparated from the drug labeling.

Some companies also are packagingdrugs in smaller quantities with theC o n s u m e r I n f o r m a t i o n S h e e t s e a l e dinside the package. Therefore, the veterinarian can just attach the hospitallabel and dosing instructions on thedrug container without repackagingthe drug and inadvertently discarding

FDA Consumer / September-Ortober 2006 / 23

FDA-Approved NSAIDs for Use in Dogs

Brand name and

e s t a b l i s h e d n a m e

M a n u f a c t u r e r /

d i s t r i b u t o r

and year of FDAapproval

I n d i c a t i o nType ofdosage

M a n u f a c t u r e r ' s

telephone numberf o r a s s i s t a n c e o r t o

report suspecteda d v e r s e r e a c t i o n

Etogesic etodolacFort Dodge AnimalHealth, 1998

management of pain andinflammation associated with

osteoarthritis in dogst a b l e t (800) 533-8536

Rimadyl carprofen

P fi z e r A n i m a l

Health, 1996(caplet); 1999(tablet); 2003(injectable)

relief of pain and inflammationassociated with osteoarthrit isin dogs; control of postoperative pain associated with softtissue and orthopedic surgeriesin dogs

caplet andchewable tablet;

injection(800) 366-5288

D e r a m a x x deracoxib

Novart is Animal

Health US Inc.,2 0 0 2

control of pain andinflammation associatedwith osteoarthritis in dogs;control of postoperative painand inflammation associatedwith orthopedic surgery in

dogs >4 lbs

chewable tab le t (800) 332-2761

M e t a c a m m e l o x i c a m

BoehringerIngelheimVetmed ica

Inc., 2003 (oralsuspension, andinjectable)

control of pain andinflammation associated withosteoarthritis in dogs

drops given bymouth; injection

(866) METACAM(638-2226)

Zubrin tepoxalinSchering-PloughAnimal Health

Corp., 2003

control of pain andinflammation associated with

osteoarthritis in dogs

rapidlydisintegrating

t a b l e t(800) 224-5318

P r e v i c o x fi r o c o x i b Merial Ltd., 2004control of pain andinflammation associated with

osteoarthritis in dogschewable tab le t (877)217-3543

N o v o xgeneric

carprofen

I M PA X L a b o r a t o r i e s

Inc./Vedco Inc.,2 0 0 5

relief of pain and inflammationa s s o c i a t e d w i t h o s t e o a r t h r i t i s

in dogscaplet (888) 708-3326

U.S Food and Drug Administration


*■ ■ Lynne Heslip and her Irish wolfhound, Isabella, compete In theshow ring before Isabella was diagnosed with hip dysplasia. Now 'retired, Isabella takes a nonsteroidal anti-Inflammatory drug(NSAID) to help relieve joint pain.

the sheet .

Through published journal articles,electronic newslet ters, and information posted on their Web sites, boththe AVMA and the AAHA are reinforc

ing the importance of client communication regarding NSAIDs, includinghanding out the Client InformationSheets, to their veterinary members.

G e t t h e R e c o m m e n d e d Te s t s

NSAIDs approved for use in dogscontain the following information onthe i r l abe l s :

All dogs should undergo a thorough history and physical examinat i o n b e f o r e i n i t i a t i o n o f N S A I D t h e r

apy. Appropriate laboratory tests to

establish baseline blood values priorto, and periodically during, the useof any NSAID are strongly recomm e n d e d .

I f the veter inar ian recommends ablood test before administering anNSAID to a dog, don't decline it,advises Sharkey. "There are good reasons for it." The knowledge gainedfrom these tests could be cri t ical in

deciding whether the drug is safe touse in a dog.

Testing is particularly importantwith long-term NSAID use, such as totreat arthritic pain, says Andrews. "Itmakes sense to do some preliminaryscreening blood work and periodictests to identify any problems and

Lynne Heslip

monitor how well the pet is toleratingthe drug over time."

W o r k W i t h Y o u r V e t e r i n a r i a n

t o F i n d t h e B e s t N S A I D

Many NSAID choices are available,and selecting the best NSAID for a particular pet is important, says Sharkey."Sometimes, the process of finding thebest one can mean changing the prescription."

Lynne Heslip of Howell, Mich., triedseveral NSAIDs on her 4-year-old Irishwolfhound, O.B., who had painfulhip dysplasia. "The first NSAID didnot work well," she says. "Pain reliefseemed to be minimal, and she hadvomiting and wasn't interested in eat-


An owner should be encouraged to call his or her veterinarianwith any concerns about the NSAID the dog is receiving.

ing." Heslij^ watched her normallyoutgoing dog seclude herself behindthe kitchen table. "She was severelydepressed. She didn't want to interactwith other animals or with people."

Working with her veterinarian, Hes-lip stopped the NSAID, waited five daysfor the drug to clear out of the dog's system, and tried another NSAID. "Withinone week, I noticed a drastic change forthe better," says Heslip. "She was muchmore animated and happier." O.B. wason NSAIDs for about three years untilher death. Heslip reports that her current 6-year-old Irish wolfhound, Isabella, is on the same NSAID, with verygood results.

Bad Reaction? Stop Medicationa n d C a l l a V e t e r i n a r i a n

If you suspect an adverse reactionto an NSAID, stop administering thedrug and contact a veterinarian immediately. Some reactions are mild and goaway after stopping the drug.

When giving a pet an NSAID, watchfor these side effects, which are listedon the Client Information Sheet andon the drug label:• Decrease or increase in appetite• Vomiting• Change in bowel movements

(such as diarrhea or black, tarry, orbloody stools)

• Change in behavior (such asdecreased or increased activitylevel, seizure, aggression, or lack ofcoordination)

• Yellowing of gums, skin, or whitesof the eyes (jaundice)

• Change in drinking habits(frequency or amount consumed)

• Change in urination habits(frequency, color, or smell)

• Change in skin (redness, scabs, orscratching).

These s ide effects are the most common. But not all possible side effectsare included on the Client InformationSheet or on the drug label. Always con

tact your veterinarian if you have questions about your dog's medication.

What starts out as a minor problemcan rapidly progress to an emergency.An owner should be encouraged tocall his or her veterinarian with anyconcerns about the NSAID the dog isreceiving. You may even call the drugmanufacturer 's to l l - f ree number thatappears on each Client InformationSheet. When problems are experiencedwith a product, the manufacturer mayhave specific recommendations foryour veterinarian regarding tests andt r e a t m e n t s .

Cindi Brinkley of Danville, 111.,rushed her dog to the veterinarian atthe first sign of a bad reaction. Maude,a cocker spaniel-collie mix, injuredherself when she was 11 months oldwhile playing with a littermate in thehouse. "She slipped on the basementfloor coming out of a turn, and bothback legs splayed out," says Brinkley.

Maude was diagnosed with adeformed hip joint and scheduled forcorrective surgery. In the meantime,the veterinarian prescribed an NSAIDfor pain control. "1 was not told a thingabout the drug other than how to giveit to her," says Brinkley.

Maude had been on the drug for amonth when Brinkley came home fromwork one day to find the dog bleedingfrom her rectum. "It was very, veryfrightening," she says. "The whole backof my dog was bright red—1 thoughtshe was bleeding to death." After treatment in the veterinary hospital anddiscontinuation of the drug, Mauderecove red f r om the i nc i den t . Now morethan 7 years old, "she has some vomiting and loose stools every so often,"says Brinkley, who suspects the digestive problems may be a lasting effectof the drug.

Report Bad ReactionsIf you or your veterinarian suspects

that an adverse reaction is related tothe use of an NSAID or any drug, it

should be reported to the pharmaceutical company. Usually, the veterinarian reports it, but if the veterinariandoesn't, the owner should. The company, by law, has to report all adversereactions to the FDA, which looks for

signals of increased frequency andseverity of adverse reactions. The FDAworks with the pharmaceutical firmsto address these events and improvethe ability of the product to be moresafely used.

If unable to report problems directlyto the pharmaceutical company, veterinarians and owners are encouraged toreport veterinary Adverse Drug Experiences (ADEs) and suspected productfailures to the government agency thatregulates the product. Adverse experiences with NSAIDs should be reportedt o t h e F D A ' s C V M . ■

Michele Sharkey, D.V.M., of the FDA'sOffice of New Animal Drug Evaluation,contributed to this article.

F o r M o r e I n f o r m a t i o nFDA Center for Veterinary Medicinewww.fda.govI cvm

American Veterinary MedicalA s s o c i a t i o n

w w w . a v m a . o r g

American Animal HospitalA s s o c i a t i o n

www.aahanet.org

Questions regardingADE reporting should bea d d r e s s e d t o :

Center for Veterinary MedicineDivision of Surveillance, HFV-2107519 Standish PlaceRockville, MD 20855(888) FDA-VETS (332-8387)


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