The Tequin Mystery
Posted by
Armand RossettiSeptember 11, 2008 2:42 PMTags:
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Tequin (gatifloxacin) is an antibiotic used to treat adults with lung, sinus, or urinary tract infections and also to treat certain bacterially generated, sexually transmitted diseases.
In recent years, reports have surfaced, concerning disturbances in glucose homeostasis that usually occurred within 3 days of initiating Tequin therapy. Most of these events were reversible although some resulted in fatal outcomes.
At times, manufacturers will submit new drug applications (NDA) to the FDA that involve label changes to institute new warnings or to make new claims about effectiveness. Between October 20 and December 27, 2005, Bristol-Myers filed an NDA for a new oral dosing regimen for Tequin that contained the following statement:
“Gatifloxacin (Tequin) exhibits in vitro minimum inhibitory concentrations (MICs) of ≤2 mcg/mL against most (≥90%) strains of the following microorganisms…; however, the safety and effectiveness of gatifloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Yet, in a study that appeared on March 30, 2006 in the New England Journal of Medicine (NEJM), investigators, not associated with Bristol-Myers, undertook an after marketing study that they started in 2003. It is curious that this retrospective study had been in progress for two years before Bristol-Myers made the statement about a lack of adequate and well controlled clinical trials to test the safety and efficacy of Tequin.
In those two years, Bristol-Myers should have had the motivation to determine whether or not Tequin was actually safe and effective.
Those independent investigators who published the March 2006 article in the NEJM took approximately three years to perform a large scale longitudinal study, and they evaluated Tequin use among a population of 1.4 million subjects. After completing the study, they arrived at the following conclusions, concerning Tequin’s connection with causing life threatening hypoglycemia and hyperglycemia:
Hypoglycemia:
“Patients treated for hypoglycemia were more than four times as likely as controls to have recently been treated with gatifloxacin as compared with a macrolide antibiotic (adjusted odds ratio, 4.3; 95 percent confidence interval, 2.9 to 6.3). We also observed a significant but weaker association between hypoglycemia and levofloxacin (adjusted odds ratio, 1.5; 95 percent confidence interval, 1.2 to 2.0). In contrast, we found no increased risk of hypoglycemia after treatment with either moxifloxacin or ciprofloxacin. As expected, we also observed no association between hypoglycemia and second-generation cephalosporins.
Similar findings were observed in analyses stratified according to drug treatment for diabetes. The association between gatifloxacin and hypoglycemia was highest among patients who were not receiving therapy for diabetes (adjusted odds ratio, 9.0; 95 percent confidence interval, 1.3 to 63.4), although this observation was based on relatively few cases. The findings were similar when we restricted the analysis to patients who were admitted to the hospital.”
Hyperglycemia:
“We identified 470 case patients who made hyperglycemia-related hospital visits after outpatient antibiotic therapy. Of these patients, 94.9 percent were matched to five controls. More than a third of them (178 [37.9 percent]) had not received treatment for diabetes within 180 days before receiving care in the hospital. The characteristics of the case patients and the controls are shown in. Their mean age was 77.4±7.4 years, and 1194 (43.4 percent) were male. The median time from the initiation of antibiotic therapy to treatment in the hospital was 5 days (interquartile range, 2 to 13). Half the case patients (233 [49.6 percent]) were treated and released from the emergency department. Of the 237 patients who were admitted to the hospital, the median length of stay was 9 days (interquartile range, 5 to 14), and 39 (16.5 percent) died before discharge.
Patients treated in the hospital for hyperglycemia were almost 17 times as likely as controls to have recently been treated with gatifloxacin as compared with a macrolide antibiotic (adjusted odds ratio, 16.7; 95 percent confidence interval, 10.4 to 26.8). In contrast, we found no evidence of an increased risk of hyperglycemia with any other fluoroquinolone or with the second-generation cephalosporins.”
The investigators also suspected mechanisms for Tequin’s action in producing both hypoglycemia and hyperglycemia and presented their hypotheses as follows:
“Although the mechanism of these apparently competing adverse effects is not fully understood, studies in animals suggest that although gatifloxacin can promote insulin release and hypoglycemia by blocking the ATP-sensitive potassium channels of pancreatic islet cells, it can also trigger the vacuolation of pancreatic beta cells, leading to reduced insulin levels and hyperglycemia.”
An NDA that Bristol-Myers filed on October 27, 2003 contained the following statement from the FDA:
“Validation of the regulatory methods has not been completed. At the present time, it is the policy of the Center not to withhold approval because the methods are being validated. Nevertheless, we expect your continued cooperation to resolve any problems that may be identified.” [Emphasis added].
In the same document, the FDA deferred until August 27, 2009, the required Tequin pediatric studies for children up to 18 years old:
“All applications for new active ingredients, new dosage forms, new indications, significant modifications of existing indications, new routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are deferring submission of your pediatric studies for Community Acquired Pneumonia caused by MDRSP in pediatric patients, ages 0 months to 18 years until June 30, 2009.”
It is also interesting to note that on July 2, 2002, the US patent Office granted Patent #US 6,413,969 (Assignee: Bristol-Myers Squibb Co.) for a new process for scaling up Tequin production. According to the statement in the patent, Tequin had already been approved. However Bristol-Myers had encountered problems when scaling the process up from a small batch full scale production:
“The initial formulation process for the preparation of tablet dosage forms containing gatifloxacin sesquihydrate was a conventional wet granulation procedure. However, when a clinical batch of such tablets failed to conform to specifications, it was discovered by Differential Scanning Calorimetry that the pattern of the bulk material used in this batch was qualitatively different from that of the earlier small scale batches, and that this difference correlated with the failure of the tablets to meet performance specifications. Further investigation revealed a complex array of transformations involving a number of hydrated and anhydrous forms of the drug, principal among which were the sesquihydrate, the pentahydrate and the hexahydrate. In all, at least twelve different crystalline forms of gatifloxacin were identified and their interrelationships mapped...”
The NEJM published the aforementioned Canadian study on March 30, 2006. Oddly enough, the FDA also issued a Tequin Alert in March 2006, concerning associated dysglycemia. However Bristol-Myers had already sought and received four label change approvals from the FDA since 2003, and had distributed a dear health care provider (DHCP) letter on February 15, 2006, that alerting health care providers about Tequin's problems concerning hypoglycemia and hyperglycemia.
It seems evident that Bristol-Myers knew that Tequin’s formulary was sensitive to large scale production (patent statement), and the FDA knew that Bristol-Myers had requested approval for four label changes. In addition, the FDA knew that Bristol-Myers had not conducted well-controlled clinical trials for Tequin. Furthermore, in October of 2003, the FDA knew that Bristol-Myers had not validated their methods. And as far back as 2000, the FDA sent a warning letter to Bristol-Myers, requesting that the manufacturer cease making false claims about Tequin’s safety and effectiveness. Yet, somehow, the FDA still found justification to push the requirement for Bristol-Myers to provide pediatric studies ahead six years, to 2009.
Fortunately in the spring of 2006, a “decline in sales” prompted Bristol-Myers withdraw Tequin from the market . However, on September 2, 2008 the FDA revealed that the actual reason behind Tequin’s withdrawal was “safety and effectiveness.”