Reported Side Effects
Most if not all drugs carry the risk of unintended side effects. Our infographic below details some of the reported side effects and references their research source.
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Urinary Tract Infections and Sepsis – FDA
Diabetic Ketoacidosis – FDA
Heart Attack and Stroke Risk – Clinical Trials
Kidney Damage and Renal Failure – Quarterwatch Report – ISMP
How Does The Drug Work?
Canagliflozin, manufactured under the brand name Invokana by Johnson & Johnson subsidiary Janssen Pharmaceutical, is one of many new-generation type 2 diabetes drugs. Known as SGLT2 inhibitors, these drugs knock out one of the kidney’s natural functions: filtering excess glucose from urine.
In patients with type 2 diabetes, the body’s cells have become “insulin resistant,” unable to utilize a hormone that converts glucose, or blood sugar, into energy. Over time, the elevated blood glucose levels that result can lead to kidney, eye, nerve and heart damage.
Invokana forces kidneys to excrete blood glucose in a patient’s urine, rather than sending the sugars back into the blood stream as they would without the drug’s influence. To learn more about the science behind SGLT2 inhibitors, which may explain some of its potential health risks, check out our in-depth guide here.
FDA Warns Of Ketoacidosis Risk
On March 15, 2015, the FDA released a major safety announcement, warning the health community about a potentially life-threatening Invokana side effect. According to the agency’s press release:
“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.”
The FDA has cautioned patients currently taking SGLT2 inhibitors to watch for signs of ketoacidosis, which include:
- nausea and vomiting
- difficulty breathing
- abdominal pain
- excessive fatigue or drowsiness
- abdominal pain
In a search of its Adverse Event Reporting System, the FDA identified at least 20 cases of ketoacidosis, diabetic ketoacidosis, metabolic acidosis or ketosis among patients prescribed SGLT2 inhibitors including Invokana between March of 2013 and June of 2014. All of these patients required emergency medical intervention or extended hospitalization. The agency reports that it has continued to receive adverse event reports linking Invokana and other SGLT2 inhibitors to these potentially fatal conditions.
To learn more about Invokana recalls, FDA warnings and regulatory action, click here.
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Major Warning Slapped On SGLT2 Inhibitors
After nearly 10 months of review, the FDA decided to take action, adding a formal warning to every SGLT2 inhibitor, including Invokana, about diabetic ketoacidosis. According to a press release issued on December 4, 2015, the new warnings will encompass ketoacidosis, “the risks of too much acid in the blood,” as well as a risk for “serious urinary tract infections.”
A review of FDA databases turned up 73 cases of ketoacidosis between March 2013 and May 2015. But the analysis also highlighted another risk, one that had slipped under the radar until now. At least 19 patients had suffered from “life-threatening blood infections […] and kidney infections.” Apparently, these infections begin as urinary tract infections and then spread, becoming more virulent, and potentially deadly, in the absence of proper medical attention. Several patients even suffered kidney failure, requiring intensive care and dialysis.
Whether ketoacidosis or kidney failure, these severe side effects invariably require hospitalization, according to the FDA. Going forward, drug manufacturers are being required to conduct enhanced studies on the risks of SGLT2 inhibitors and will have to follow up with patients who report severe side effects for the next 5 years.
Update June 15, 2016 – FDA Warns Of Link To Acute Kidney Injury
In a new safety alert, the FDA has announced updated warnings for two SGLT2 inhibitors, Invokana and Farxiga. Over the last two years, both drugs have been implicated in at least 101 confirmed cases of acute kidney injury, a syndrome in which kidney function deteriorates suddenly. The condition, also known as AKI, can lead to total organ failure and even death if left untreated.
To learn more about the FDA’s recent warnings, click here.
Growing Use & Rising Problems
Long-term safety data is sorely lacking, reports the Institute for Safe Medication Practices (ISMP), a nonprofit drug watchdog that’s been on Invokana’s case since before the drug’s approval. But the drug’s popularity can’t be doubted. Data from the leading clearinghouse for pharmaceutical sales shows that Invokana broke 1.1 million outpatient prescriptions in the second quarter of 2015, a three-month period between April and June. Other SGLT2 inhibitors have seen similar, though not quite blockbuster, success. Farxiga reached 411,000 prescriptions in the same period, while Jardiance was prescribed 136,000 times.
As more and more patients were exposed to SGLT2 inhibitors, the ISMP noted a proportionate increase in adverse event reports submitted to the Food & Drug Administration. During 2015, the FDA reportedly received:
- 5,484 side effect reports involving Invokana
- 1,805 side effect reports involving Farxiga
- 455 side effect reports involving Jardiance
Cases of ketoacidosis, the ISMP says, still represent a relatively small fraction of these total reports, but since the prevalence of complications has increased in step with total prescriptions, the numbers likely support a causal link between these drugs and DKA.
Ketoacidosis Cases Increase – As Do Infections
Remember that the FDA could identify only 73 cases of ketoacidosis between 2013 and May of 2015, and further, that those 73 cases were likely split between Invokana, Farxiga and Jardiance. For the full calendar year of 2015, on the other hand, the ISMP identified:
- 168 possible DKA cases associated with Invokana
- 80 possible DKA cases associated with Farxiga
- 12 possible DKA cases associated with Jardiance
Far more prevalent are genital fungal infections, like yeast infections, which were widely reported in clinical trials conducted prior to Invokana’s approval. In those studies, 11.4% of female subjects and 3.7% of males experienced infections. Since SGLT2 inhibitors increase the amount of glucose present in the bladder and urine, this side effect is not altogether surprising. Fungi favor environments high in sugar, which can be an energy source for virulent bacteria as well. As we mentioned earlier, the FDA has observed a number of serious urinary tract infections in Invokana patients. While those infections are caused by bacteria, unlike fungal infections, the increased incidence of both infection types among patients taking SGLT2 inhibitors may have, at the bottom, the same cause.
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Does Invokana Increase Risk For Kidney Failure?
While the FDA’s recent emphasis on kidney failure has surprised many in the medical community, Invokana has actually been linked to various forms of renal damage for the last year.
In May 2015, the Institute for Safe Medication Practices reported that “early signals for [Invokana] raise questions about whether enough is known about this agent to be assured that its benefits outweigh its risks.”
Reviewing adverse event reports submitted to the FDA, ISMP identified a total of 457 “serious adverse event reports,” including severe impairment of kidney function. The reports, all submitted during the second quarter of 2014, included:
- 54 reports of kidney failure or impairment
- 54 reports of dehydration and fluid imbalances
- 11 reports of kidney stones
- 50 reports of urinary tract infections
- 52 reports of abnormal or other weight loss
- 50 reports of hypersensitivity (allergic reactions)
Perhaps most surprisingly, the ISMP wrote that many of these potential side effects could have been “reasonably anticipated,” in light of the drug’s effects on kidney function and the results of clinical data. ISMP reports that studies conducted prior to Invokana’s approval using animal subjects revealed evidence of “long-term kidney damage, kidney and testicular cancers and bone abnormalities.”
To learn more about Invokana’s possible risk of kidney damage, click here.
Could The Drug Present Cardiovascular Risks?
In March 2013, a meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee convened to discuss the safety and efficacy of Invokana. Noting that the drug’s approval was based on studies that indicated “no evidence of any improved clinical outcomes” over older diabetes medications, noted patient advocate Dr. Sidney Wolfe highlighted “a number of serious safety signals identified in [Invokana’s] clinical trials.”
Wolfe emphasized an apparent increase in the rate of “cardiovascular events,” particularly blood clots which can quickly lead to stroke. Using data from studies on another SGLT2 inhibitor, Wolfe demonstrated how patients taking Invokana experienced much higher increases in red blood cell concentration, a common precursor to the development of blood clots.
Two FDA officials seconded Wolfe’s concerns, noting increased rates of cardiovascular “events” among patients prescribed Invokana. Dr. Mat Soukop, an FDA biostatistician, cited a clinical trial in which patients administered the drug were 6.9 times more likely to experience cardiovascular complications than patients given a placebo.
Invokana was approved two months later.
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Competition May Reduce Cardiovascular Risks
In a strange twist, one of Invokana’s direct competitors is being floated as a treatment for diabetes-related cardiovascular complications. Jardiance, an SGLT2 inhibitor manufactured by Eli Lilly, has been shown to cut heart disease deaths in patients with type 2 diabetes by a significant margin. Diabetes is a primary contributor to cardiovascular complications, including stroke and heart attack, but Jardiance seems to help. A recent clinical trial, published in the November 2015 edition of the New England Journal of Medicine, found that Jardiance reduced the risk of death from cardiovascular causes by 38%.
Patients used for the trial were picked specifically because they already had cardiovascular diseases, and thus lived at an increased risk of heart attack and stroke. The results, however, were far more ambivalent than the reduction in total deaths would imply. The incidence of stroke actually increased among Jardiance patients, while the reduction in heart attacks was deemed “statistically insignificant.” So what did Jardiance do? It reduced the likelihood of heart failure when the heart loses the ability to pump blood properly.
After the study’s publication, stock in Eli Lilly jumped by 7%, according to the New York Times. Without similar data in support of Invokana, stock in Janssen’s parent company Johnson & Johnson fell by 1% the same day.
Contact Banville Law’s Attorneys
For now, Invokana’s patient safety remains in serious doubt. But with an estimated 2 million Invokana prescriptions written in 2014 alone, numerous Americans may be at risk of developing the drug’s severe potential side effects.
For patients who took Invokana and suffered ketoacidosis, kidney failure or any other serious adverse event, legal action may be possible. The legal community anticipates that many injured patients may choose to file lawsuits, and while it is unlikely that an Invokana litigation would result in class action, a high volume of claims may increase the likelihood of future Invokana settlements.
The experienced attorneys at Banville Law are here to help. If you believe that Invokana caused ketoacidosis, kidney failure or cardiovascular complications, contact our lawyers today for a free consultation.
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