Parker Waichman LLP Injury Alerts
Cymbalta - Another Unneeded Antidepressant of Questionable Value That Poses Significant RisksFeb 1, 2006
In January 2005, Public Citizen, the well-known consumer watchdog group, published an article in Worst Pills Best Pills News (vol. 11, No. 1, p.1) titled “DO NOT USE – Duloxetine (CYMBALTA) For Major Depressive Disorder – Nothing Special And Possible Liver Toxicity.”
While the headline says it all, a closer look at the drug is warranted since it presents yet another prime example of an unnecessary, expensive, and potentially dangerous alternative to perfectly acceptable existing medications.
Cymbalta is an antidepressant manufactured by pharmaceutical giant Eli Lilly & Co., the company that already produces Prozac. It was approved by the Food and Drug Administration in August of 2004.
Not long after its release, however, side-effects such as liver damage and suicidal behavior began to appear. In addition, Lilly was accused of telling medical professionals to withhold negative information about Cymbalta from patients.
In October 2004, just a few months after Cymbalta was approved, the FDA ordered that a stronger warning about the serious risk of suicide be placed on the drug’s label.
In fact, all antidepressants including Anafranil, Aventyl, Celexa, Desyrel, Effexor, Elavil, Lexapro, Limbitrol, Ludiomil, Luvox, Marplan, Nardil, Norpramin, Pamelor, Parnate, Paxil, Pexeva, Prozac, Remeron, Sarafem, Serzone, Sinequan, Surmontil, Symbyax,Tofranil, Tofranil-PM, Triavil, Vivactil, Wellbutrin, Zoloft, and Zyban now carry a “black-box” warning label, the strongest drug warning issued by the government.
While these other antidepressants were certainly under scrutiny by the FDA, Cymbalta attracted further attention based on unfavorable results from clinical trials. It was discovered that the rate of suicide attempts was more than doubled for women taking Cymbalta to treat stress urinary incontinence.
Cymbalta is not yet approved for this usage in the United States, although 30 other countries, including most of Europe, have already approved the drug to treat incontinence.
In the study of women taking Cymbalta for incontinence, 11 of nearly 9,000 women tried to commit suicide. It is significant to note that these patients were not suffering from depression prior to beginning treatment with Cymbalta.
The drug companies are quick to argue that increased rates of depression associated with antidepressants are understandable since the patients are already depressed and potentially suicidal before they begin treatment. In this case, however, the drug companies’ argument is unavailing to explain the increased incidence of suicide.
The controversy began when Traci Johnson, a healthy volunteer involved in a trial at Eli Lilly's clinic at Indiana University Medical Center in Indianapolis, committed suicide. Johnson did not suffer from depression prior to the study. She was taken off the drug and given a placebo four days before she killed herself.
Johnson was the fifth patient to commit suicide after taking Cymbalta in clinical trials. Since her death, one-fifth of the volunteers have quit the Cymbalta trial.
In addition to the heightened risk of suicide, new data has linked Cymbalta to possible liver damage. New warnings about liver damage have been added to the drug’s label.
Hepatoxicity was already listed as a potentially severe side-effect of Cymbalta. Patients who consume a substantial amount of alcohol on a regular basis and patients with chronic liver disease are advised to consider an alternate treatment for their depression.
While these two serious health risks are reason enough to question the safety of Cymbalta, Eli Lilly’s behavior in regards to advertising its product through media and through doctor/patient conversations is also troubling.
In November 2005, the FDA told Eli Lilly & Co. that it had failed to make the risks of its Cymbalta medicine clear enough in medical journal advertisements that promoted the drug to treat nerve pain caused by diabetes. In a letter to Lilly, the agency said the company should stop running the ads. The FDA said the ads are considered Cymbalta promotion even though their main panels do not mention the drug.
Cymbalta, also used as an antidepressant, has risks that include dementia if used with older antidepressants known as monoamine oxidase inhibitors. It also can spur allergic reactions according to the FDA.
Insurers and prescribers are also concerned with what appears to be questionable practices on the part of Eli Lilly. Lilly allegedly offered health facilities and other purchasers of large quantities of antidepressants, a 5% discount in drug prices for Cymbalta if they agreed to refrain from making “unflattering statements” about the risks associated with the drug when conferring with medical professionals.
The Cymbalta discount contract also states that insurers, hospitals, and other medical facilities could lose their discount if they engage in what is known as “negative D.U.R. correspondence” with physicians.
D.U.R. is an industry term for “drug utilization review,” a type of analysis of prescription patterns that is often used to point out inappropriate or dangerous practices. D.U.R.s are also used to cut costs.
Another restriction in the Cymbalta contract is “negative educational counterdetailing” which basically means that insurers are not allowed to counterbalance sales pitches made by drug companies. Counterdetailing tends to steer patients more towards generic drugs or to dissect claims made by drug makers about their drugs.
Some insurers are concerned that the Cymbalta contract would have a negative effect if it succeeds in preventing insurers and other groups from being truthful about medical information regarding Cymbalta.
Lilly argues that this contract is an effort to cut costs to make Cymbalta more affordable and available to patients who need it. Lilly believes that its interest in controlling negative D.U.R. communications is legitimate and warranted. A spokesperson for Lilly says that the Cymbalta contract is not intended to prevent communications that are “backed up by clinical data and presented in a fair and balanced manner.”
The controversy surrounding Cymbalta continues to grow and the drug has only been on the market for a year and a half. Although it is somewhat comforting to know the FDA is making sure that the proper warnings are placed on the drug’s label and that Lilly is being monitored to some extent with respect to the marketing of Cymbalta, the overall situation is just another example of questionable practices in the approval process that allow drugs to be released the market before an adequate amount of clinical testing has been conducted.
While the public should be spared another Vioxx-like debacle, rushing drugs to market through the fast-track approval process that is more than 50% funded by the pharmaceutical industry has not worked. The failure to perform longitudinal studies with large study groups has led to withdrawal after withdrawal in recent years. Post-marketing failures in testing and reporting have also hampered efforts to protect the public.
Cymbalta may very well turn out to be yet another prescription drug with a short-term success story that could not stand up to the reality of widespread, long-term use by real patients. Between 1997 and the beginning of 2005, 19 drugs have been withdrawn from the market. These include:
- Palladone (hydromorphone) – 2005
- Bextra (valdecoxib) – 2005
- Tysabri (natalizumab) – 2005
- Vioxx (rofecoxib) – 2004
- Duragesic Patch (fentanyl transdermal patch) – 2004
- Ephedra – 2004 (withdrawal order vacated by a federal judge)
- Baycol (cerivastatin) – 2001
- Raplon (rapacuronium bromide) – 2001
- Rezulin (troglitazone) – 2000
- Propulsid (cisapride) – 2000
- Lotronex (alosetron) – 2000
- Hismanal (astemizole) – 1999
- Raxar (grepafloxacin) – 1999
- Posicor (mibefradil) – 1998
- Duract (bromfenac) – 1998
- Seldane (terfenadine) – 1997
- The Diet “Cocktail”: Fen-Phen (fenfluramine); Pondimim; and Redux (dexfenfluramine) - 1997
For purposes of presenting the view expressed by Public Citizen with respect to Cymbalta, we have reproduced the following excerpt from the January 2005 article in Worst Pills Best Pills referred to in the opening paragraph:
“Duloxetine (Cymbalta) is classified as a serotonin and norepinephrine reuptake inhibitor (SNRI) or dual reuptake inhibitor. As one physician observer of drugs used to treat serious mental illness has noted, duloxetine has ‘dual the reuptake, triple the hype.’ The other SNRI inhibitor on the market is venlafaxine (EFFEXOR).
Our major safety concern with duloxetine is the possibility of liver toxicity. The FDA medical officer that reviewed the drug found a small but statistically significant excess of discontinuations of treatment due to liver-related adverse events in patients treated with duloxetine compared to those given a placebo in clinical trials conducted before the drug was approved.
In his conclusions and recommendations regarding duloxetine’s liver toxicity, the medical officer wrote:
In the event that unconfounded cases of severe liver injury or acute liver failure related to duloxetine treatment are identified and submitted early in the post-marketing period, the division will use the threshold of three ‘clean’ cases to initiate additional regulatory action that could range from a more prominent warning to the withdrawal of the drug product.
This is a remarkable statement. The FDA obviously has serious concerns about the safety of duloxetine, yet they still allowed it on the market. By approving duloxetine, the FDA has made the American public guinea pigs in a large uncontrolled safety experiment. Because duloxetine is nothing special and there are numerous options to treat major depressive disorder in adults, the proper course of action for the FDA should have been to require the manufacturer to conduct more studies to clarify the liver toxicity issue before approving the drug.
The FDA-approved professional product labeling, or package insert, for duloxetine does warn pharmacists and physicians about an increased risk of elevations in blood levels of liver enzymes. Elevations in liver enzyme levels are an early signal of possible liver toxicity. However, there is no requirement in the professional product labeling that physicians monitor liver enzymes. Physicians are cautioned not to prescribe duloxetine to patients who regularly use alcohol because of the possibility of liver toxicity.
Blood pressure elevation is another area of concern with duloxetine. The FDA medical officer recommended that:
Patients taking duloxetine should be monitored regularly for hypertension (high blood pressure). There is evidence for a dose dependent increase in the incidence of elevated blood pressure with duloxetine treatment. These increases do not appear to pose an acute risk; however, given that the treatment of Major Depressive Disorder (MDD) is chronic in nature, patients’ blood pressures could easily drift into ranges that are associated with increased risk of heart disease and stroke. 24% of patients taking duloxetine 120-mg/day (milligrams per day) experienced elevated blood pressures versus 9% of placebo patients.
The FDA-approved professional labeling for duloxetine advises that blood pressure be measured prior to starting treatment and periodically measured throughout treatment.
Duloxetine and all of the other antidepressants marketed in the U.S. now carry warnings in their professional product labeling about worsening of depression and an increased risk of suicide. Patients being treated with antidepressants should be observed closely for worsening of their depression and suicidal ideation and behavior, especially at the beginning of a course of drug therapy, or at the time of either increases or decreases in dose changes.
Duloxetine is not approved for use in children or adolescents with major depressive disorder. The drug’s professional product labeling contains the following uninformative statement about the use of duloxetine in children and adolescents ‘Safety and efficacy in pediatric patients have not been established.’ This could mean that the drug failed in clinical trials in this age group but the manufacturer decided not to make the results public. The bottom line is that duloxetine has not been shown to be of therapeutic benefit in younger patients.
Abruptly stopping duloxetine treatment can result in a withdrawal syndrome that consists of the following symptoms: dizziness; nausea; headache; a sensation of pricking, tingling, or creeping on the skin (paresthesia); vomiting; irritability; and nightmare. Discontinuation of duloxetine should only be done under medical supervision.
Duloxetine was approved by the FDA on the basis that it was more effective than a placebo, in other words, better than nothing. One of the games that pharmaceutical manufacturers play when their new drug is only better than nothing is to create an image that the new drug has unique effects compared to other similar drugs in its family. In the case of duloxetine, Eli Lilly is trying to claim that the drug has special value in managing the painful symptoms of major depressive disorder.
At this time, any claim that duloxetine is useful for managing pain is groundless.
The Medical Letter on Drugs and Therapeutics a source we frequently cite because of its independence from drug company influence, found that duloxetine was ‘nothing special’ and concluded their October 11, 2004 report by saying:
Whether duloxetine offers any advantage over venlafaxine (EFFEXOR) or an SSRI [selective serotonin reuptake inhibitor] such as fluoxetine (PROZAC, and others) remains to be established. The manufacturer’s claim that duloxetine is the antidepressant for painful physical symptoms associated with depression is unsupported; no comparative trials are available.
What You Can Do
There is no medical reason why you should be taking duloxetine when safer antidepressants are available on the market.
Do Not Discontinue Cymbalta Treatment Abruptly — Gradual Discontinuation Of This Drug Must Take Place Under Medical Supervision.
If you suspect that you or a loved one has suffered an injury as a result of taking Cymbalta, another antidepressant, or any drug listed on our Web site, please do not hesitate to contact us at www.yourlawyer.com for a free case evaluation.