Indianapolis-based multinational pharma firm Eli Lilly & Co, has prevailed the first court trial in a series of lawsuits and class actions alleging that the company has failed to provide adequate warning of potential serious side-effects associated with terminating use of its antidepresant drug Cymbalta (duloxetine).

Cymbalta is a relatively new antidepressant medication manufactured by Eli Lilly & Co. that was frist was approved by the U.S. Food and Drug Administration to treat major depressive disorder and brought to market in 2004. Belonging to a class of antidepressant drugs known as “serotonin and norepinephrine reuptake inhibitors” (SSRIs/SNRIs) Cymbalta was initially prescribed to treat symptoms associated with major depression, with approval subsequently expanded to include generalized anxiety disorder, fibromyalgia, chronic low back pain, chronic osteoarthritis pain and diabetic nerve pain. Use of Cymbalta as a treatment for fibromyalgia pain in has become popular due to impressive results experienced by many patients.

However, lawyers representing plaintiffs in some 250 of lawsuits from people who experienced severe withdrawal symptoms upon cessation of Cymbalta therapy contend that potential side effects associated with use of this drug have been under-advertised and minimized on warning labels by the manufacturer, noting that Cymbalta has been linked to onset of significant and debilitating mental disturbances including mania, suicidal thoughts and insomnia, and that Cymbalta patients additionally are at risk of developing chronic liver problems, seizures, nausea or dizziness. The legal argument is that drugmakers bear responsibility for warning patients of the statistical likelihood of certain conditions or side effects that may result from use of their products, and that failure to do so exposes the drugmaker to liability for patients who experience side effects for which they were not warned.

The plaintiffs allege that while in its prescribing directives Lilly warned that at least one percent of Cymbalta users experience withdrawal, citing studies such as a 2005 study designed, conducted and funded by Lilly, and published in the Journal of Affective Disorders entitled “Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder” (DOI: http://dx.doi.org/10.1016/j.jad.2005.09.003), coauthored by David G. Perahia of the Lilly Research Centre at Windlesham, Surrey, UK and the Gordon Hospital, London, UK; Daniel K. Kajdasz and Durisala Desaiah of Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, and Peter M. Haddad of the University of Manchester, UK Neuroscience and Psychiatry Unit; who found that up to 51 percent of Cymbalta users experienced discontinuation symptoms, which were severe in 10 to 17 percent of cases, and in over 50 percent of these patients, withdrawal reactions had not resolved by the end of the study’s two week withdrawal period. The researchers conclude that abrupt discontinuation of duloxetine is associated with a discontinuation-emergent adverse events (DEAEs) profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants, and recommend that, whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment.

In its directive for Cymbalta discontinuation the National Institutes of Health U.S. National Library of Medicine says:

“Do not stop taking duloxetine without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking duloxetine, you may experience withdrawal symptoms such as nausea; vomiting; diarrhea; anxiety; dizziness; tiredness; headache; pain, burning, numbness, or tingling in the hands or feet; irritability; difficulty falling asleep or staying asleep; sweating; and nightmares. Tell your doctor if you experience any of these symptoms when your dose of duloxetine is decreased.”

For its part, Eli Lilly & Co. maintains that there have been too few severe Cymbalta withdrawal cases to justify creation of a Multi-District Litigation (MDL) for Cymbalta lawsuits that would centralize litigation in the U.S. District Court for the Central District of California, as had been requested by plaintiffs in 28 California cases. The MDL process resembles a class action in that it centralizes a litigation in one court in which plaintiffs coordinate the discovery process and conduct “bellwether” trials. However, unlike a class action, each lawsuit remains independent and can have its own particular outcome.

Eli Lilly & Co. spokespersons were cited commenting that “The MDL procedures should not be utilized to create a ‘field of dreams’ that attracts a swath of meritless claims that can be shielded from individualized discovery under the Federal Rules,” the company arguing that antidepressant withdrawal is a “well-recognized” side effect, and suggesting that convincing a jury that physicians were unaware of the risk will be a “formidable task.”

That contention appears to have been accurate. In a Friday, August 7, news article Reuters’ Jessica Dye reports that a California jury last week cleared Eli Lilly of liability in the first Cymbalta withdrawal trial that started last Tuesday, with the jury returning its verdict on Friday.

The jury appears to have agreed with Eli Lilly’s “well-recognized side effect” contention, with it having been known since at least 2001 that antidepressants, opiates, benzodiazepines, and other psychiatric medications can cause withdrawal symptoms when patients stop taking the drug “cold turkey,” and it being pretty much standard practice for doctors to recommend gradually tapering off dosage of these drugs over sometimes considerable lengths of time.

Failure to taper off drugs like Cymbalta and many others can result in nasties like development of potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions, which have been reported with termination of therapy with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) and other drugs that impair serotonin metabolism (including Monoamine oxidase inhibitors or “MAOIs” — an older class of antidepressants), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). In its most severe form Serotonin Syndrome, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

Council for plaintiffs in the Cymbalta lawsuits maintain that withdrawal risk was widely downplayed by Eli Lilly despite knowledge that users could die from its use, and that notwithstanding its decision to place a warning on the drug in 2005, it continued to market and sell Cymbalta as a safe and reliable treatment option for conditions like anxiety disorder, fibromyalgia and depression. Meanwhile, they allege that “thousands” of Cymbalta victims were experiencing excruciating and debilitating symptoms upon withdrawal from Cymbalta therapy even when tapering slowly from the drug under a doctor’s supervision.

Eli Lilly’s Prescribing Information insert for Cymbalta (most recently updated in 2009) Section 5.6 “Discontinuation of Treatment with Cymbalta” notes that:

“Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, fatigue, paresthesia, vomiting,
irritability, nightmares, insomnia, diarrhea, anxiety, hyperhidrosis and vertigo.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., parenthesis such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable
symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the
dose but at a more gradual rate [see Dosage and Administration (2.4)]”

Section 2.4 – “Discontinuing Cymbalta” says:

“Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.”

Section 2.5 – “Switching Patients to or from a Monoamine Oxidase Inhibitor” adds:

“At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI”

Eli Lilly contends those warnings constitute due diligence on its part.

Lawyers for lawsuit plaintiffs point to Eli Lilly’s failure to mention “withdrawal” as a potential Cymbalta discontinuation symptom, which can range in intensity from mild discomfort resembling the flu to severe symptoms that can be potentially life threatening as grounds for liability.

The jury in the first case to be tried has sided with the company. It remains to be seen if juries in subsequent cases agree with that precedent.

Sources:
National Institutes of Health U.S. National Library of Medicine
Eli Lilly and Company
The Journal of Affective Disorders
Cymbalta Attorney (http://cymbaltasideeffects.com)
Reuters
Law360
Salient News