Alopecia Warning Added 20 Years Too Late?
On December 11, 2015, Taxotere’s Prescribing Information was updated with a brief mention of the drug’s risks for persistent alopecia in the “common side effects” section:
“in most cases normal hair growth should return. In some cases (frequency not known) permanent hair loss has been observed.”
In the “post-marketing experiences” section, patients are now informed that “cases of permanent alopecia have been reported.” Shockingly, prior to this update, the U.S. label for Taxotere didn’t include any mention of the possibility that patients could lose their hair indefinitely. Alopecia was merely included as a common side effect or adverse reaction, with no clarifications on how long hair loss could potentially last.
European Label Had Hair Loss Warning In 2010
Considering Taxotere was first released in the U.S. in 1996, this recent warning has come far too late to benefit thousands of patients who have already received the drug. And although American patients have been left in the dark until now, Taxotere’s label throughout Europe has included permanent alopecia warnings for years – apparent evidence that Sanofi was already aware of these risks long ago yet withheld this knowledge from the American public.
Worse yet, Taxotere’s label used to assure patients that “hair generally grows back” after treatment is completed, likely leading many to believe that the drug only causes temporary hair loss, just like any other chemotherapy agent. However, this statement was quietly removed on May 13, 2010, shortly after alopecia warnings were added to the Taxotere label in Europe.
Studies Cited In Taxotere’s European Label
At least as early as 2009, European labeling for Taxotere included the statement “cases of permanent alopecia have been reported” in its post-marketing data section. Also, in a table on “very common adverse reactions,” a less than 3% incidence of persisting alopecia is listed under “skin and subcutaneous tissue disorders.”
This <3% incidence figure (which is relatively low compared to more recent estimates of 6% to 15% from various post-market Taxotere research studies) was calculated based on pooled data from early clinical trials that examined Taxotere’s effectiveness and possible adverse effects. The results of these trials were already made available to consumers in Europe back in 2005, in a “scientific discussion” on Taxotere’s efficacy and side effects. Two trials in particular, which are comprehensively summarized in Taxotere’s European label, provided revealing follow-up data on persistent alopecia:
The TAX 316 trial focused on a group of 1,491 patients with operable node-positive breast cancer. The patients were selected at random to either receive a “TAC” regimen of doxorubicin, cyclophosphamide, and docetaxel (Taxotere), or an “FAC” regimen of doxorubicin, cyclophosphamide, and fluorouracil. Each regimen was administered every 3 weeks for 6 cycles. This trial yielded positive results for Taxotere by demonstrating that the TAC regimen resulted in longer disease-free survival, reduced rates of cancer relapse, and higher overall 10-year survival rates in comparison to the FAC regimen.
But trial participants in the TAC group also experienced an elevated incidence of side effects, including persistent alopecia. 29 out of 744 TAC patients (3.9%) still suffered from alopecia at the end of the study’s follow-up period versus only 16 out of 736 (2.2%) of patients on the FAC regimen. The median follow-up time for participants was 8 years—clearly demonstrating that these patients were indeed suffering from persistent alopecia.
In this study, 1,060 patients with operable node-negative breast cancer randomly received adjuvant treatment of either a TAC or an FAC regimen, also administered every 3 weeks for 6 cycles. Analyses of the results after a median 125-month follow-up period showed that the TAC group experienced 16.5% less risk of relapse than the FAC group, as well as a positive but statistically insignificant trend in disease-free survival rates for the TAC patients.
Regarding persistent alopecia, 49 out of 532 (9.2%) of TAC-treated patients still struggled with “ongoing” alopecia during the roughly 10-year follow-up period.
Did Sanofi Conceal Permanent Alopecia Risks?
These clinical trials were an early indication that Taxotere presents a higher-than-normal risk of persistent alopecia compared to any other chemotherapy drugs. One would think that a roughly 3% chance of developing permanent hair loss should have been significant enough to warrant at least some mention on Taxotere’s label right from the start.
After all, any adverse drug effects that occur with a frequency between 1% and 10% are considered “common” according to standards followed by the European Medicines Agency, which the FDA also uses as a rough guideline for side effect classifications. For context, a higher than 10% incidence is dubbed “very common”; 0.1% to 1% “uncommon”; 0.01% to 0.1% “rare,” and so on.
But why would Sanofi choose to omit a permanent alopecia warning from Taxotere’s U.S. label even while releasing such warnings in Europe and Canada (in May 2012)? According to recent lawsuits filed by Taxotere hair loss victims, the omission was a component of “fraudulent” promotion methods that Sanofi used to manipulate American consumers into considering Taxotere superior to any competitor drugs.
Plaintiffs Say Sanofi Intentionally Misled The Public
According to these patient lawsuits, Sanofi didn’t merely overlook its duty to inform patients of Taxotere’s permanent hair loss risks, but rather intentionally concealed these and other important safety data in order to make the drug appear more appealing to healthcare providers, the American public, and even the FDA. Plaintiffs say that because of this concealment and other forms of deception performed by Sanofi, “thousands of women were exposed to the risk of disfiguring permanent alopecia without any warning and without any additional benefit.”
The lawsuits draw supporting evidence for their fraud accusations from a Qui Tam lawsuit (commonly known as a “whistleblower” case) filed by former Sanofi employee Yoash Gohil back in 2001. Gohil, who worked as a Sanofi sales representative from Feb 1982 up until he resigned from the position in June 2002, drew heavily upon his insider experience with Sanofi’s “corrupt” hidden corporate policies to expose a “fraudulent marketing scheme” that he says the company used to promote Taxotere for off-label purposes and unlawfully gain funds from government programs.
Selling More Taxotere – At Any Cost?
During the period that Gohil worked for Sanofi, Taxotere was only FDA-approved for a few indications—second-line treatment of breast cancer and non-small cell lung cancer. Yet he says the company’s Oncology Sales division routinely promoted Taxotere use for over 15 other non-approved indications, as well as encouraging potentially unsafe, excessive dosages in order to sell more of the drug.
Gohil claims that a high volume of off-label sales was achieved through:
- Giving “illegal kickbacks” such as fake grants, free dining, and entertainment, speaking fees, and free samples to physicians and other medical professionals in exchange for prescribing off-label Taxotere and submitting fraudulent reimbursement claims to Medicare and Medicaid programs
- Training sales personnel to “overstate” Taxotere’s effectiveness and safety while downplaying its risks through strategic use of flawed or biased studies
- Distributing advertising materials containing misleading language as well as blatant falsehoods about Taxotere’s approved scope of application and demonstrated efficacy
Whether or not Gohil’s allegations are true, Sanofi did receive multiple warnings from the FDA for distributing “misleading” print ads and other promotional materials for Taxotere.
FDA Demands Sanofi Pull Taxotere Ads
In July 2001, the Division of Drug Marketing, Advertising, and Communications (DDMAC), the branch of the FDA that regulates marketing, sent a letter to Sanofi (named Aventis at the time) concerning a set of Taxotere brochures distributed at the company’s commercial booth during an annual meeting of the American Society of Clinical Oncology (ASCO).
These brochures, according to this first FDA letter, falsely advertised treatment with Taxotere and Adriamycin as “the only taxane combination approved for first-line treatment of metastatic or locally-advanced breast cancer.” This statement was untrue on two counts—
- there were other taxane combinations approved for that indication at the time
- Taxotere wasn’t actually approved as a first-line treatment. It was approved as a second-line treatment.
The FDA demanded that Sanofi “immediately cease the distribution of these and similar promotional materials.” But the company went on to receive a number of additional warnings in the following years:
- 2002. The FDA sent another letter about Taxotere brochures. Again, the FDA found a number of “false and misleading claims” featured in the brochures, as well as weak data from less-than-rigorous studies and “manipulative data presentation.” Overall, the agency strongly felt that Sanofi was exaggerating Taxotere’s efficacy and downplaying its risks, and feared that the brochures would “compromise patient survival and safety.” Sanofi responded to this letter and assured the FDA that it would destroy these materials and stop using the advertising tactics the FDA objected to.
- 2003. Yet again, the FDA reprimanded Sanofi for Taxotere advertising, saying that despite Sanofi’s promises, the company was distributing brochures “substantially similar” to the ones that the FDA took issue with the previous year. For example, these new advertising materials boasted positive results from Taxotere that were calculated from a smaller subset of patients within a larger study. But now Sanofi was going even further by proclaiming that Taxotere held “significant survival advantage” over competitor drugs and implying that patients who don’t take Taxotere “will not survive.”
- 2009. Years later, Sanofi was at it again with problematic advertising and received another warning letter. This time, the FDA complained of a “reprint carrier”—a binder containing reprints of medical studies—that displayed exaggerated claims about Taxotere’s effectiveness. According to the text on the reprint carrier, a 2005 study found that Taxotere could “outperform” Taxol in treating metastatic or locally advanced breast cancer. But the FDA noted that the study in question did not find a statistically significant advantage of Taxotere over Taxol, nor were any other studies able to replicate such an advantage, rendering Sanofi’s claims of superiority “unsubstantiated.”
Obviously, the possibility that Sanofi withheld an alopecia warning from the American public would appear consistent with earlier accusations of misleading marketing. For now, all we can make is an educated guess, as the whistleblower lawsuit and the growing list of patient lawsuits are still awaiting trial.
Will FDA Issue A Permanent Alopecia Warning?
Unfortunately for prospective Taxotere users, probably not. The FDA generally only distributes urgent Safety Communications for potentially dangerous side effects. Because hair loss doesn’t pose a safety threat, the FDA will likely never issue such a warning about Taxotere-induced permanent alopecia, despite the negative impact the condition can have on patient well-being and quality of life.
However, the FDA did publish a safety warning about another potential side effect, and Taxotere recalls have been issued in Canada and more recently in Europe:
FDA: Alcohol In Taxotere Could Intoxicate Patients
On June 20, 2014, the FDA alerted the public about alcohol levels in Taxotere, which may be high enough to cause intoxication. Doctors were urged to carefully consider the ethanol content in Taxotere (the alcohol dissolves the drug’s active ingredient, enabling intravenous administration), especially in the case of patients taking other medications that may have adverse interactions with alcohol. Patients were warned to wait for 1-2 hours after receiving a Taxotere infusion before performing tasks such as driving and operating machinery.
To help patients avoid this potential safety threat, manufacturers are in the process of developing an alcohol-free formulation of docetaxel.
Health Canada: Overfill Of Solvent Led To Diluted Batches
Prompted by complaints from Finland and Sweden, Health Canada recalled a batch of Taxotere on October 30, 2006. According to the alert, the affected units may have been of a lower concentration than normal due to an error in filling solvent vials during production.
EMA: Over-Concentrated Taxotere From Production Error
The European Medicines Agency announced on April 20, 2016, that Sanofi is recalling 15 batches of Taxotere due to a “software failure” at a Sanofi manufacturing plant in Germany that may have caused too much alcohol to evaporate, raising the concentration of the affected vials.
The EMA believes the recall may temporarily cause a Taxotere shortage in France, Ireland, Italy, and Spain, but supply is expected to return to normal on August 19, 2016.
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