2,300 families blame the drug Neurontin for suicide or suicide attempts

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This is just a very small tip of the iceburg. Many millions aredamaged each year by drugs and almost all are "not reported"."Zeus" 2,300 families blame the drug Neurontin for suicide orsuicide attemptsTue, 3 May 2005 22:06:00 +01002,300 families blame the drug Neurontin for a suicide or suicideattempt and are taking legal steps against its maker, Pfizer Inc.Rick Crone was the rock in his family.The Marine veteran -- and father of two -- handled much of the care ofhis disabled wife, Nicolette, for the more than two decades they weretogether.But in 2001, Rick's spirits plummeted, an ominous change Nicolettesaid she first noticed after he started taking a new prescription forback pain. His upbeat personality faded over the next months, and lateone night in April 2002 as his family slept, the 49-year-old fatherwalked into the garage and hanged himself.Unknown to the family in Clearlake (Lake County), Nicolette Cronelater said, was that the medicine, Neurontin, was an epilepsy drug. Ithad been prescribed to Rick "off label" because treating back pain wasnot a use approved by the Food and Drug Administration.She now is among 2,300 families who blame Neurontin for a suicide orsuicide attempt and are taking legal steps against its maker, Pfizer Inc.And she is part of a growing chorus saying that patients should betold when a treatment has not been through the FDA's rigorous approvalprocess. No law requires doctors to disclose to their patients thatthey are prescribing a drug for an off-label use.Pfizer, which sold $2.7 billion worth of Neurontin last year, deniesthat the drug caused suicides, stating that comprehensive data overthe past decade "refute any suggestion that Neurontin causesdepression, suicidal thoughts or suicidal behavior."The FDA, however, recently asked Pfizer and 13 other manufacturers tolook for signs of suicide risks in data on Neurontin and other drugsfor epilepsy.In addition to epilepsy, Neurontin is approved to treat pain from askin ailment known as shingles. But the vast majority of Neurontin'sprescriptions are for off-label uses, such as bipolar disorder and --as was Rick Crone's case -- back pain.Off-label prescriptions are legal and common, encompassing a widerange of drugs, from skin creams to anti-depressants to cancertherapies. A 1992 American Medical Association study estimated that 40to 60 percent of prescription drugs were given for unapproved uses.Although off-label uses can be valuable, even lifesaving, some arebacked only by flimsy studies. In other cases, off-label treatmentsonce favored by doctors have later proved to be harmful, even deadly.Many patients, however, aren't aware of this. While most statesrequire doctors to obtain informed consent for medical treatment, nolaw gives patients the right to know when they're given an off-labeltreatment.Whether doctors should make that disclosure is a question relevant toall patients, because off-label prescriptions are so widespread.Billions of dollars are spent every year on these treatments thatdrugmakers and many doctors praise as innovative medicine, but criticsliken to experiments on unwitting guinea pigs.The real impact on individual patients can be hard to gauge, becausethe treatments are tried outside the controlled conditions of clinicaltrials.Rick Crone's doctors had him on other painkillers besides Neurontin --not unusual in the treatment of back pain. His wife, alarmed by hisslide into depression, had urged him to get his prescriptions reduced.His death left Nicolette Crone, 45, grief-stricken and struggling tocope as a single mother who uses a wheelchair because of injuries inher youth. She's also dealing with her children's pain. Rick Crone'sbody was found by the child he called his "little angel,'' hisdaughter, Cassie, then 13. Hearing her cries, Rick's 16-year-old son,Ben, rushed in and desperately tried to save his dad.Whatever level of suicide risk, if any, the FDA finds for Neurontin,millions more people will have been exposed to that risk than therelatively small number of patients who received it for its twoapproved conditions.Whether those patients who took it off label -- for ailments includingmigraine headaches, psychiatric illnesses and restless leg syndrome --received any benefits while bearing Neurontin's risks is open todebate because the drug was never evaluated by the FDA for those uses.And whether the benefit outweighed the risk also is in question. Apatient trying to control seizures might be willing to accept fairlyserious side effects, but someone taking the same drug for a headacheor back pain might find those risks unacceptable.Like many family members who are now raising questions about off-labeltreatments, Nicolette Crone believes patients deserve to know whentheir prescriptions are not for FDA-approved uses."Why didn't they tell us?'' she said. "One person's life affects somany others.''Armed with the knowledge that a prescription was off label, proponentssay, patients might ask more questions; seek other sources ofinformation, such as the Web; watch more closely for side effects; orask for an approved treatment instead.But doctors say such a disclosure would only scare patients, possiblyspurring them to refuse a medicine they sorely need.Faith in the sober judgment of physicians, however, has been shaken byrecent revelations of illicit drug industry tactics to influencedoctors and distort the scientific evidence available to them aboutoff-label uses.Federal prosecutors charged last year that Neurontin's multibillion-dollar market arose from illegal strategies such as paying doctors topromote it off label for dozens of conditions, from back pain topsychiatric illnesses. The case was settled with a $430 million fineand guilty pleas by a Pfizer unit.Another drugmaker, GlaxoSmithKline, was accused last year of buryingstudies on its anti-depressant Paxil while encouraging doctors toprescribe it off label to children. The studies indicated the drugdidn't work well in adolescents and might be linked to cases of suicide.Lawyers representing thousands of families in personal injury casesinvolving Neurontin, or anti-depressants such as Paxil, say none oftheir clients were told the drugs were given off label.If doctors don't voluntarily reveal when their prescriptions are offlabel, patients can always bring up the issue. But it's not a questionmany people would think to ask.A 2004 poll commissioned by a division of the Wall Street Journalsuggests that most Americans are assuming every prescription isFDA-approved. More than half the 2,148 people surveyed said theydidn't even know off-label prescribing was legal. Another 17 percentweren't sure.In fact, once a drug is FDA-approved for even a single disease, it canbe legally prescribed for any other ailment. Although the FDA candistribute advisories to doctors and issue warnings of drug sideeffects, it does not directly regulate the practice of medicine -- arole filled by state governments.The FDA does, however, forbid most promotion of off-label uses by drugmanufacturers until they conduct studies to support the agency'sapproval for that new use.Off-label treatments not only include prescribing a drug for a newdisease, but also significantly changing the dose, combining it withother treatments, or using the drug in a new population, likechildren, not named on the original FDA label.Mainstream physician groups such as the American Medical Associationsay off-label treatments sometimes provide the best possible care. Forexample, the well-known antiviral drug AZT, originally a cancertreatment, was used off label for a time before it was approved todelay the onset of AIDS in HIV- infected people. Many doctors alsopoint to the beta blockers, medicines approved to lower blood pressurethat also were used to decrease the risk of death after a heart attack.Some off-label treatments, however, have been linked to deaths orsevere side effects, like the heart valve damage caused by thediet-drug regimen known as fen-phen. Hormone replacement therapy, amenopause treatment, was once prescribed to millions of women in thebelief it would ward off cancer and stroke. Major studies have sincefound the drugs actually increase those risks.The range of risks and benefits with off-label treatments, though notclearly known, probably varies widely. Some unapproved uses may bebacked only by inconclusive studies, while others are supported byhigh-quality research.Arthur Levin, executive director of the Center for Medical Consumersin New York, said patients cannot give truly informed consent tomedical treatment without knowing when a therapy is off label."If it's not an approved use, they're taking it experimentally,''Levin said. "They should know that, and decide whether they want toparticipate.''If Rick Crone had been a participant in a formal research trial on theeffect of Neurontin for back pain, the scientific investigators wouldhave been required by federal statutes to inform him that thetreatment was experimental and obtain his consent in writing.But when the same drug is prescribed off label in ordinary medicalpractice, the requirements for patient consent -- governed by statelaws -- are far less stringent.In California, physicians don't always need written consent, but theymust outline the benefits and potential risks of the drug. State lawalso generally requires doctors to disclose other information theythink a reasonably prudent patient would need to make an informeddecision.But whether that means a doctor is obliged to reveal a proposedtreatment's off-label status would depend on the particular facts inthat case. A jury in a malpractice suit might decide either way, saidHans Lee, a staff attorney for the California Medical Association.One Oakland woman thinks the law needs to change. After Maddy Oden's32- year-old daughter, Tatia, died in 2001 during labor induced by anunapproved treatment, she became an advocate for hard-and-fastgovernment rules requiring doctors to tell patients every time theyprescribe off label.Oden found out to her dismay that doctors continue to use the ulcerdrug Cytotec off label to induce labor, in spite of a 2000 warning bythe drugmaker that Cytotec could cause a pregnant woman's uterus torupture. Doctors maintain the drug can be used safely with carefulmonitoring.A visit from Oden spurred California Assemblywoman Loni Hancock latelast year to consider framing a state law that would make off-labeldisclosure by doctors mandatory."I would want to know it,'' Hancock, D-Berkeley, said at the time. "Itwould lead me to ask other clarifying questions. For example: Is thereanother drug that is approved for this use or this population, likechildren? What evidence is there that this off-label drug is better,or that it's safe?''Hancock's office began by focusing on rules for the off-label use ofCytotec and found conflicting opinions among doctors and women'sgroups. No bill is on the table, but Hancock said she will continue towork on the issue.Physicians who believe strongly in giving their patients fullbriefings about a drug's known benefits and risks may neverthelessquail at the idea of telling them the treatment is off label. Thereason often given: fear of scaring patients away from a remedy thedoctor believes could be the best possible alternative.This reluctance can be found even among doctors credited with helpingprevent injuries from off-label uses.Dr. Raymond Woosley, a University of Arizona pharmacology expert, tookpart in renowned clinical studies in the late 1980s that proved twoheart drugs promoted for off-label use actually increased the risk ofdeath.But Woosley doesn't see an advantage in doctors discussing atreatment's off-label status with patients. The off-label use may lackFDA approval for any of a variety of reasons unknown to the doctor, hesaid -- perhaps because the company simply couldn't afford to applyfor an expanded FDA approval."Doctors can't manage that information, and patients can't either,''he said. "A patient may refuse a drug that could be very valuable.''A spokesman for the international trade association for biotechnologyfirms, the Biotechnology Industry Organization, said an off-labeldisclosure law would hamstring doctors, harm patients and sink biotechfirm revenues."We have a lot of products that are cancer products, and a majority oftheir use is off label," said Jayson Slotnik, the biotechorganization's director of Medicare reimbursement and economic policy.He said a disclosure law would make doctors hesitant to usenon-FDA-approved treatments.The major trade association representing large drugmakers, thePharmaceutical Research and Manufacturers of America, said suchlegislation might be consistent with the group's policies promotingpatient awareness, depending on how the law was implemented.A prominent industry lawyer maintains that doctors should have noobligation to disclose off-label status because it is irrelevant intheir discussions with patients. Off label doesn't automaticallysignal a higher level of risk, said James Beck, who wrote aninfluential 1998 law review article on the issue. Beck argues thatoff-label treatments include those that are widely accepted as thestandard of care. At the same time, some drugs prescribed forFDA-approved uses have later been found to cause unforeseen harm."All medical treatments, including off-label treatments, have medicalrisks, and patients must be informed of medical risks,'' Beck wrote.Consumer advocates and drug regulators, on the other hand, say doctorsmay be hard-pressed to inform their patients of the risks oftreatments never reviewed by FDA standards. The thorough studies thatmight identify those risks, in a new patient population with adifferent disorder, often have not been conducted, they say.A prime example is the state of knowledge about adult drugs used offlabel in children, said Dr. Dianne Murphy, director of the FDA'spediatric drug development office. Awareness began growing in the1960s that the results of adult studies do not necessarily predict howthe developing bodies of children would react to drugs, Murphy said."I think it's really wrong to say you have the same level of knowledgefor a product being used off label than ones that have beenapproved,'' Murphy said.Some parents, unaware their children were given unapproved treatments,are now haunted by questions they didn't know to ask. Parents wouldrather learn up front about all possible risk factors than anguishover their decisions later, one father said.Jay Baadsgaard, a Washington state farm employee, now spends hours onthe Internet researching the anti-depressants his 15-year-old son wastaking off label in 2001 when he brandished a hunting rifle duringclass. Fortunately, the boy didn't shoot anyone.Baadsgaard supports mandatory disclosure when a prescription is off label.But Baadsgaard said people don't have to wait for a change in the lawto get fuller information from the doctor -- including the FDA statusof a drug."We have to remember he's working for us, and we can ask him anyquestion we want,'' Baadsgaard said. "If we don't get the answer, wecan get up and leave.''What does 'off label' mean?"Off label'' is a shorthand term for a drug or medical procedure thatis prescribed for a use other than the approved use on its Food andDrug Administration label. For example, a doctor might prescribe adrug approved to treat one disease, like cancer, as a remedy foranother condition, like psoriasis. Or a drug approved in adults mightbe prescribed off label for children. A change in an approved drugdose, or a surgical procedure that is modified, can also be anoff-label use.Ask your doctorOff-label prescriptions are widespread, encompassing a vast spectrumof medicines. Such drugs are sometimes the best treatment available.In other instances, they have been linked to severe side effects. Ifyou're not sure whether the drug you've been prescribed is off labelor not, ask your doctor. If it is, here are some more specificquestions you could ask (but bear in mind these aren't the typicalquestions that physicians hear).-- Has the FDA approved this treatment for people with my condition?For my age group? At this dosage level? For this duration of time?-- What sources of information did you draw on to decide that this wasright for me?-- What are the benefits and risks, and how can they be known withoutFDA evaluation? Does the off-label treatment have dangerousinteractions with other remedies used for my condition?-- Are there alternative treatments for my condition that are FDA-approved? What are their benefits and risks?The lowdown on off-label treatmentsWhat are the limitations on off-label drugs?Once a drug has FDA marketing approval for at least one ailment, itcan be legally prescribed for any other disease. However, doctors areexpected to choose these treatments based on sound evidence. If theydo not, they may be vulnerable to malpractice suits.Drug companies are generally forbidden from promoting their productsfor off-label use. They can earn the right to advertise drugs foradditional uses if they submit studies to the FDA proving that the newuse is safe and effective.How prevalent are off-label drug prescriptions?Estimates of the size of the off-label drug market range from 20 to 60percent of the nation's $235 billion annual prescription-drug bill.Off-label use is highest in certain fields like oncology. Doctorsoften try unapproved remedies against life-threatening diseases likecancer when approved therapies are no longer effective.Why are off-label drug prescriptions so common?The FDA does not require manufacturers to obtain approval for allconditions where a drug may have some value. The approval process isexpensive, and a drugmaker may decide to forego it when, for example,the new use would bring in just a few extra customers afflicted with arare condition. In addition, most drugs are tested only in adults toobtain approval. Therefore, the majority of drugs given to childrenare off label in that population.Beyond that, prosecutors have accused some drug firms of drumming uphuge off-label sales through illegal promotion.For patients, what are the benefits of off-label drugs?A use unapproved by the FDA may nevertheless be regarded by doctors aseffective. Doctors base these judgments on their own clinicalexperience, the opinions of their colleagues, published studies andinformation from drug company sales representatives. Patients maybenefit from the early use of a drug that is expected to win FDAapproval soon for a new use that is supported by high-quality research.The actual benefits of many off-label drugs, however, may never beknown unless the manufacturer or outside researchers conductwell-designed clinical trials like those required by the FDA. Somemedical studies relied on by physicians are too small or too badlydesigned to prove that a use is effective.What are the risks?As with the benefits, the risks of off-label drugs may be largelyunknown. Factors that are considered in depth when the FDA approves adrug for its original indication may never be systematically studiedfor an off-label use. These factors include the appropriate dose totreat the new disease; the possible side effects for people withdifferent health problems; and any potentially dangerous interactionsbetween the drug and other remedies taken for that new illness.Off-label drugs have been linked at times to deaths or severe sideeffects, such as blindness and heart damage.Children can respond to drugs very differently from adults, sometimeswith dangerous consequences. The FDA is now encouraging manufacturersto test all drugs in children, though such studies are not required.What is the law regarding the disclosure of off-label drug prescriptions?No law in any state contains language specifically requiring doctorsto tell their patients when a prescribed treatment is off label. Insome states, including California, judges may allow injured patientsto use a doctor's lack of disclosure to bolster a malpractice suit.Other state courts have ruled that the failure to disclose theoff-label status of a treatment is irrelevant in malpractice claims.In California: what doctors must tell patientsDoctors in California must obtain informed consent to medicaltreatment, though this does not necessarily mean written consent. Thephysician is required to outline the benefits and any serious risks ofa drug or procedure.Beyond that, doctors are responsible for disclosing other informationthat they know, or should know, would be needed by a reasonable personto make an informed decision to accept or reject the treatment.California law does not explicitly require doctors to reveal that theyare prescribing a drug off label. But a jury in a malpractice casemight conclude, in some cases, that the patient needed thatinformation to make an informed choice. If a jury reached thatconclusion, the liability could be increased for a physician whodidn't disclose the drug's off-label status.Chronicle researchTroubled treatmentsHere is a sampling of some of the more high-profile off-labelcontroversies.Drug (maker)Paxil (GlaxoSmithKline)FDA- approved use: Antidepressant for adultsCommon off-label use: Antidepressant for children New York AttorneyGeneral Eliot Spitzer sued the firm, saying it suppressed dataindicating that Paxil could increase the risk of suicide in children.The company settled the lawsuit in 2004, agreeing to post negativestudy results online, but admitted no wrongdoing.Drug (maker)Neurontin(Pfizer)FDA- approved use: Treating epilepsy and pain related to shingles, askin disorder Common off-label use: Treating back pain, bipolardisorder and many other illnesses Controversy: Drug was illegallypromoted for dozens of off-label uses; company pleaded guilty lastyear to federal felonies related to marketing and agreed to pay thegovernment a $430 million fine.Drug (maker)Prempro/other hormone replacement therapy(Wyeth)FDA- approved use: Treating symptoms of menopause and preventingosteoporosis Common off-label use: Once prescribed widely in thebelief it would ward off heart disease, stroke, cancer and otherdiseases of agingControversy: Large-scale clinical trials in recent years have foundthat the hormone pills increased the risks of heart disease, stroke,breast cancer and dementia. Use of the drugs, if necessary, is nowrecommended for only the shortest possible amount of time.Drug (maker)Fen-phen: Pondimin and Redux (American Home Products/Wyeth), orfenfluramine, used with phentermine -- a generic diet drugFDA- approved use: Fenfluramine was approved as a short-termdiet drugCommon off-label use: The "fen-phen" combination of diet drugs wasused off label in long-term weight loss regimensControversy: Pondimin and Redux were withdrawn from the market in 1997after the Mayo Clinic found heart valve damage among those takingfen-phen.Drug (maker)Enkaid (Bristol Myers) and Tambocor (3M-Riker)FDA- approved use: Treating life-threatening cases of irregular heartbeatCommon off-label use: Prescribed in the 1980s for people withless-serious cases of "skipped heartbeat."Controversy: A large government study found in 1989 that the drugsmore than tripled the risk of death when given to patients withless-serious cases of irregular heartbeat -- a use now discontinued.forwarded byZeus Information ServiceAlternative Views on Healthwww.zeusinfoservice.com