Invokana, Johnson & Johnson's new type 2 diabetes drug, has been hailed as a "revolution" in blood glucose management. Rather than motivating the liver to produce more insulin, Invokana forces kidneys, which would normally return glucose to the blood stream, to excrete blood sugars as "waste" instead.
But along with a host of other medications known as SGLT2 inhibitors, Invokana has been associated with a potentially fatal side effect: ketoacidosis.
The condition, common among type 1 diabetes patients who cannot use glucose as an energy source, occurs when fat cells are broken down as an alternative fuel. But the resulting source of energy, ketones, are a type of blood acid.
Dangerously high levels of ketones can literally poison patients, leading to coma and even death.
Ketoacidosis is extremely rare in type 2 diabetes patients. And since Invokana is only approved for the treatment of type 2 diabetes, the FDA took immediate notice after receiving an abnormally high proportion of adverse event reports in which SGLT2 inhibitor patients had suffered from forms of ketoacidosis.
The agency responded to this serious danger sign by issuing a Safety Communication on May 5, 2015, "warning that the type 2 diabetes medicines canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis, a serious condition where the body produces high levels of blood acids called ketones that may require hospitalization."
After eight months of heightened vigilance, the FDA has decided to strengthen the warning label on Invokana - and all other SGLT2 inhibitors - to reflect evidence of the drugs' link to ketoacidosis. In a press release announcing the decision, the agency wrote:
"A U.S. Food and Drug Administration (FDA) safety review has resulted in added warnings to the labels of a specific class of type 2 diabetes medicines called sodium-glucose cotransporter-2 (SGLT2) inhibitors about the risks of too much acid in the blood"
Any patients who notice symptoms of ketoacidosis, like nausea and fatigue, have been advised to stop taking Invokana immediately and seek medical attention. The agency emphasized the condition's severity and noted that its onset may not be associated its other common warning sign: high blood sugar.
The FDA is requiring drug manufacturers, among them Janssen Pharmaceuticals, the company responsible for Invokana, to conduct a five-year study on "spontaneous postmarketing reports of ketoacidosis in patients treated with SGLT2 inhibitors."
More surprising, the FDA has decided to add a second new warning to Invokana's label for severe urinary tract infections. In reviewing adverse event reports, the agency identified 19 patients who had contracted "life-threatening blood infections [fusion_builder_container hundred_percent="yes" overflow="visible"][fusion_builder_row][fusion_builder_column type="1_1" background_position="left top" background_color="" border_size="" border_color="" border_style="solid" spacing="yes" background_image="" background_repeat="no-repeat" padding="" margin_top="0px" margin_bottom="0px" class="" id="" animation_type="" animation_speed="0.3" animation_direction="left" hide_on_mobile="no" center_content="no" min_height="none"][...] and kidney infections." Apparently, these infections began as fairly routine UTIs, but then quickly spread to the bloodstream or kidneys.
The FDA believes Invokana has something to do with this increased virulence, but no specific mechanism has been suggested to explain the link. Each of the 19 patients required hospitalization, and several were placed on dialysis to prevent kidney failure.
Canagliflozin is the active ingredient in Invokana, and in combination with metformin, an older diabetes drug, is also marketed by Johnson & Johnson's subsidiary Janssen Pharmaceutical as Invokamet.
But the FDA made clear that other SGLT2 inhibitors also carried the risk for ketoacidosis:
In its press release, the FDA said that it was "continuing to investigate this safety issue and will determine whether changes are needed in the prescribing information for this class of drugs, called sodium-glucose cotransporter-2 (SGLT2) inhibitors."
On September 10, 2015, the FDA published a new announcement, warning patients and doctors that Invokana may decrease bone density, primarily in the hip and lower spine.
Pooling data from nine clinical trials, the agency found a marked increase in bone fractures, broken bones, among patients prescribed Invokana. However, broken shoulders, arms, hands, and fingers were observed more frequently than fractures in the lower extremities.
The FDA added new warnings, along with study information, to Invokana's warning label.
Even earlier, the agency showed signs that Invokana's potential side effects would receive more scrutiny than those of other pharmaceuticals. Upon the drug's approval in 2013, the FDA announced that it had ordered Janssen to conduct 5 additional post-marketing studies:
For context, the agency approved a total of 37 new drugs in 2013. But the agency only announced that it was requiring post-marketing studies for four, not including Invokana. And three of those four drugs were also approved for the treatment of type 2 diabetes.
The FDA gave Janssen several years to complete the additional Invokana studies; the cardiovascular outcomes trial is expected to end in June of 2017.
Neither Janssen Pharmaceutical nor its parent company Johnson & Johnson have issued a recall of Invokana.
Invokana has also been linked to kidney impairment, including kidney failure, and concerns over a potential risk of blood clots and stroke were voiced two months before the drug's approval in 2013. But even if additional research supports an association between Invokana and these potential safety issues, the drug may never be recalled.
In 2007, Steven Nissen, MD and Kathy Wolski, MPH, both researchers affiliated with the Cleveland Clinic, performed a large meta-analysis of studies investigating the potential link between GlaxoSmithKline's Avandia and cardiovascular risks. Avandia, a diabetes drug that promotes proper insulin function, was linked to a 43% increase in the risk of myocardial infarction, or heart attack.
Nissen and Wolski analyzed the results of 42 clinical trials, making their study of Avandia's risks the most comprehensive to date. Many critics raised their voices in support of a recall, but Avandia remains on the US market.
Rather than enforcing a withdrawal of the drug, the US Food & Drug Administration forced GlaxoSmithKline to revise Avandia's warning label. In an attempt to limit Avandia's prescription (the drug was once one of America's best-selling pharmaceutical products), the FDA added a "Black Box" warning to its prescribing information: "Thiazolidinediones, including rosiglitazone [Avandia's active ingredient], cause or exacerbate congestive heart failure in some patients." The FDA also restricted actual distribution of the drug but never asked GlaxoSmithKline to recall it.
Once Avandia's link to cardiovascular complications was revealed, former patients who had suffered heart attacks brought a wave of legal claims against GlaxoSmithKline. By 2010, more than 13,000 Avandia suits had been filed; most were settled by the company before an FDA review board decided to restrict the diabetes drug's sales further, by making it unavailable at retail pharmacies.
But this massive litigation spurred a New York Times investigation. Eventually, Times reporter Gardiner Harris discovered that a series of GlaxoSmithKline's own clinical trials had found evidence of Avandia's cardiovascular risks as early as 1999. On July 13, 2010, Harris wrote: "instead of publishing the results, the company spent the next 11 years trying to cover them up."
These revelations led the US Department of Justice to file its own lawsuit against GlaxoSmithKline, claiming that the company had failed to report critical safety data about Avandia to the FDA. The company settled the Federal Government's case in 2012, agreeing to pay a total of $3 billion.
As in the case of Avandia, the full story on Invokana may only come to light after injured patients begin to file lawsuits. Several patients have already stepped forward, initiating legal actions against the drug's manufacturer.
Banville Law, a personal injury firm devoted to protecting patient rights, has begun to investigate potential Invokana lawsuits. Our experienced attorneys are offering free consultations to any patient who suffered ketoacidosis or kidney failure after being prescribed an SGLT2 inhibitor.
For more information and a case eligibility evaluation at no charge, contact Banville Law today.[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]