Drug Injury Watch

Invokana / Farxiga / Jardiance: Urinary Tract Infections Leading To Urosepsis And Pyelonephritis Are Lesser Known Side Effects

To Date, More Attention Paid To The Association Between These Sodium-Glucose Cotransporter-2 Inhibitors And Diabetic Ketoacidosis Or Acute Kidney Injury

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Over the past year the FDA has mandated several drug label changes for Invokana, Farxiga, and Jardiance, as well as Invokamet, Xigduo, Glyxambi, and Synjardy, to increase the warnings about some serious side effects linked to these relatively new diabetes medicines.  And the FDA is currently investigating additional adverse reactions that may be associated with these sodium-glucose cotransporter-2 (SGLT2) inhibitors drugs.

To date, most attention has been directed to the association between the SGLT2 inhibitors and diabetic ketoacidosis. For example, see this December 2015 article, "FDA Adds Ketoacidosis Warnings To Diabetes Drugs Invokana, Farxiga, And Jardiance As Well As Other SGLT2 Inhibitors".

More recently, there was an FDA announcement concerning a label change about the acute kidney injury side effect, as covered in this June 2016 article, "Invokana, Invokamet, Farxiga, Xigduo: Warnings About Acute Kidney Injury Risk Are Increased On Revised Drug Labels For These Diabetes Medicines".

What has received less attention, it seems, is the fact that these still relatively new diabetes drugs -- Invokana, Farxiga, and Jardiance, as well as their several "combination" products -- have been linked to serious urinary tract infections (UTIs) that can result in more severe conditions, such as urosepsis and pyelonephritis.

For presenting some of the leading information about these side effects we turn to this source, "FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections", issued on December 4, 2015.

From the "Safety Announcement" part of that document we get an introduction to this set of safety problems for Invokana, Farxiga, and Jardiance:

A U.S. Food and Drug Administration (FDA) safety review has resulted in adding 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 and of serious urinary tract infections. Both conditions can result in hospitalization....

... symptoms of a urinary tract infection, such as a feeling of burning when urinating or the need to urinate often or right away; pain in the lower part of the stomach area or pelvis; fever; or blood in the urine. Contact a health care professional if you experience any of these symptoms....

We also identified 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as urinary tract infections with the SGLT2 inhibitors reported to FAERS from March 2013 through October 2014. All 19 patients were hospitalized, and a few required admission to an intensive care unit or dialysis in order to treat kidney failure.

 

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Next, we move to a part of that FDA document titled "Additional Information for Patients":

Serious Urinary Tract Infections

• Before taking an SGLT2 inhibitor, inform your health care professional if you have a history of problems urinating; or infections in the bladder, kidneys, or urinary tract.
• Contact your health care professional right away if you have any signs or symptoms of a urinary tract infection such as:
  • A burning feeling when urinating
  • A need to urinate often
  • The need to urinate right away
  • Pain in the lower part of your stomach area (pelvis)
  • Blood in the urine
• Sometimes patients may also have a fever, back pain, nausea, or vomiting.

And for the purpose of going more in-depth about the apparent increased risk of serious urinary tract infections (UTIs) associated with these SGLT2 inhibitor diabetes drugs, we get the following details from the "Data Summary" section of this December 2015 'FDA Drug Safety Communication:

A search of FAERS from March 2013 through October 2014 identified 19 cases of urosepsis reported with the SGLT2 inhibitors [Invokana (canagliflozin)] [n=10] and [Farxiga (dapagliflozin)] [n=9]). All cases resulted in hospitalization. No deaths were reported. Four patients required admission to the intensive care unit, and two required hemodialysis to treat renal failure. The median time to onset was 45 days (range 2 to 270 days). Discontinuation of the SGLT2 inhibitor was reported in 15 cases. Details regarding whether or not there was a prior history of urinary tract infection was not available for most of the cases. Eight of the 19 reports documented blood culture results with E. coli as the isolated organism in each. Eleven cases contained no information about blood culture testing. There were no reports of fungal urosepsis. Details regarding the administered antibiotic agent, course of antibiotic treatment, and evidence of relapse or recurrent infection were not provided in any of the cases.

We are currently investigating possible drug injury lawsuits against the responsible pharmaceutical companies for diabetes patients using SGLT2 inhibitor diabetes drugs who have developed side effects such as diabetic ketoacidosis, acute kidney injury, and serious urinary tract infections (UTIs) that led to urosepsis or pyelonephritis. For more information, see our Invokana / Farxiga / Jardiance / Invokamet / Xigduo / Glyxambi / Synjardy page.

 

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review done by attorney Tom Lamb) 

Summer 2016 Update On Diabetes Medicines Invokana / Farxiga / Jardiance: Drug Label Changes And Safety Investigations

According To Drug Regulators, New Possible Side Effects Include: Fatal Cases Of Ketoacidosis; Leg, Foot, And Toe Amputations; And, Lactic Acidosis

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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UPDATE: Invokana "Black-Box Warning" For Leg And Foot Amputations 

"FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)"

[5-16-2017] Based on new data from two large clinical trials, the U.S. Food and Drug Administration (FDA) has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. We are requiring new warnings, including our most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk.

See also: "Risk of Lower Limb Amputations Doubled with Invokana and Invokamet Use" from our Drug Safety Developments blog.

(5/18/17)

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On June 14, 2016 the FDA announced it has strengthened the existing warning about the risk of acute kidney injury for Invokana and Invokamet as well as Farxiga and Xigduo XR. These relatively new diabetes drugs are known as Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors.

Notably missing from this June 2016 drug safety warning were Jardiance (empagliflozin), Glyxambi (empagliflozin and linagliptin), and Synjardy (empagliflozin and metformin hydrochloride), which are also part of the SGLT2 Inhibitors class of drugs.

About a month later, however, only those three diabetes drugs from Boehringer Ingelheim Pharmaceuticals, Inc. received a Supplemental Approval letter from the FDA concerning a label change about ketoacidosis, an apparent serious side effect. Using the July 8, 2016 FDA letter for Jardiance as a representative document showing this most recent revision to the safety information for these drugs:

Please refer to your Supplemental New Drug Application (sNDA) dated and received February 12, 2016....

This Prior Approval supplemental new drug application proposes to amend the Jardiance Prescribing Information and Patient Information with new text informing that fatal cases of ketoacidosis have been reported in patients treated with [Jardiance (empagliflozin)].

APPROVAL & LABELING

We have completed our review of this supplemental application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text.

To be clear, a virtually identical letter was sent by the FDA to Boehringer Ingelheim for fatal cases of ketoacidosis being associated with Glyxambi and Synjardy.

 

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Invokana / Farxiga / Jardiance

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As regards a different side effect and going back in time a bit, to mid-May 2016, we point out this document, "FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate".

From the Safety Announcement section of that document we get this information:

The U.S. Food and Drug Administration (FDA) is alerting the public about interim safety results from an ongoing clinical trial that found an increase in leg and foot amputations, mostly affecting the toes, in patients treated with the diabetes medicine canagliflozin (Invokana, Invokamet). We have not determined whether canagliflozin increases the risk of leg and foot amputations. We are currently investigating this new safety issue and will update the public when we have more information.

Since then, we have not heard again from the FDA about the results of this investigation regarding leg, foot, and toe amputations possibly caused by the use of Invokana and Invokamet. But recently the European Medicines Agency (EMA)'s Pharmacovigilance Risk Assessment Committee (PRAC) announced that their investigation about such amputations now includes all the diabetes medicines in the SGLT2 Inhibitors class of drugs, such as Farxiga and Jardiance.

For more about this recent EMA action, I refer you to this article, "All SGLT2 Inhibitors Now Investigated for Increased Risk of Amputation", over at our Drug Safety Developments site.  I point out that this article contains some insightful commentary from a medical expert about the so-called "mechanism of injury" for these leg and toe amputations that have been linked by some to Invokana, Farxiga, Jardiance and similar new diabetes drugs.

Last but not least, in May 2016 there was what is commonly called a Black-Box Warning about lactic acidosis added to the label for Invokamet, as seen on this FDA Safety Information page, "Invokamet (canagliflozin and metformin HCl) Tablets".

The May 2016 revised Invokana label know includes this drug side effect warning information:

• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain....
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

We will continue to monitor the safety profile for this SGLT2 Inhibitors class of drugs, watching for future label changes with increased side effects warnings, the results of safety investigations by the FDA and the EMA, etc.

 

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

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Summer 2016 Update On ED Drugs Viagra / Cialis / Levitra: Medical And Legal Developments

Melanoma Skin Cancer: FDA Is Evaluating The Need For Regulatory Action; More Lawsuits Filed; Another Research Study

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE: IN RE: Viagra (Sildenafil Citrate) and Cialis (Tadalafil) Products Liability Litigation, MDL-2691 --  As of the first part of January 2017 there were 263 Viagra and Cialis cases filed according to the document "MDL Statistics Report - Distribution of Pending MDL Dockets by District -- Report Date: 1/17/2017", issued by the United States Judicial Panel on Multidistrict Litigation.

(2/16/17)

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In late June 2016 the Food and Drug Administration (FDA) said it will study a potential link between melanoma skin cancer and erectile dysfunction (ED) drugs such as Viagra, Cialis, and Levitra.

This announcement appeared in the agency's latest watch list of drugs with possible safety issues, "January - March 2016: Potential Signals of Serious Risks/New Safety Information Identified from the FDA Adverse Event Reporting System (FAERS)". In relevant part, the document listed these drugs which have been associated with melanoma as a serious side effect.

PDE-5 inhibitors:

Adcirca (tadalafil; Eli Lilly and Company): tablets

Cialis (tadalafil; Eli Lilly and Company): tablets

Levitra (vardenafil hydrochloride; GlaxoSmithKline): orally disintegrating tablets

Revatio (sildenafil citrate; Pfizer): tablets, oral suspension, and injection

Staxyn (vardenafil hydrochloride; GlaxoSmithKline): orally disintegrating tablets

Stendra (avanafil; Vivus and Auxilium Pharmaceuticals): tablets

Viagra (sildenafil citrate; Pfizer): tablets

From this July 1, 2016 Medscape article, "New FDA Watch List: Possible ED Drug–Melanoma Link and More", we get some background information about that June 2016 FDA investigation announcement:

The agency will be on the heels of other researchers when it comes to the class of ED drugs called phosphodiesterase (PDE)-5 inhibitors. A study published in JAMA Internal Medicine in April 2014 found an association between sildenafil and an increased risk for melanoma. However, the authors said their epidemiological evidence was not strong enough to change clinical recommendations for treating ED.

Likewise, a study published in JAMA in June 2015 did not nail down a cancer risk for these drugs. Mining a massive health database of Swedish patients, the authors reported that among 4000 men diagnosed with malignant melanoma, use of a PDE-5 inhibitor was linked to a 20% increase in the relative risk for the cancer.

On the legal front, a growing number of Viagra - melanoma lawsuits have been filed against the drug company Pfizer. The federal court cases were consolidated in April 2016 before U.S. District Judge Richard Seeborg in the Northern District of California. Those Viagra cases are now part of a multidistrict litigation which often goes the short name "Viagra federal court MDL 2691".

 

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In more detail, from the April 7, 2016 Transfer Order  (PDF document) issued by the United States Judicial Panel on Multidistrict Litigation (JPML): "These actions share actual questions arising out of the allegation that Viagra (sildenafil citrate) causes or increases the risk of developing melanoma and that Defendant failed to warn consumers and health care providers of the alleged risk."

As regards the general nature of these Viagra - melanoma lawsuits, many of the filed Complaints include allegations along these lines:

• Pfizer knew Viagra posed a cancer risk and purposely concealed facts regarding the drug’s safety;
• Pfizer failed to sufficiently investigate the link between Viagra and an increased risk of melanoma prior to
  FDA approval; and,
• Pfizer failed to warn users about the link between Viagra and the increased risk of melanoma even after studies showed the
  association, and instead continued promotion of the product.

And that last point brings us back to the medical developments concerning melanoma and the use of Viagra, Cialis, Levitra, and other medicines in the PDE-5 inhibitor class of drugs.

According to a study published in mid-June 2016 by the journal PLOS Medicine, some researchers from the UK found that men who took Viagra, Cialis, and Levitra had only a very slight increase in the risk of developing melanoma compared to a control group, with that risk appearing to be explained by greater exposure to the sun (as opposed to these ED drugs).

From the Abstract for this medical journal article, "Phosphodiesterase Type 5 Inhibitors and Risk of Malignant Melanoma: Matched Cohort Study Using Primary Care Data from the UK Clinical Practice Research Datalink", we get this overview of that medical research. We start with the Background section

Laboratory evidence suggests that reduced phosphodiesterase type 5 (PDE5) expression increases the invasiveness of melanoma cells; hence, pharmacological inhibition of PDE5 could affect melanoma risk. Two major epidemiological studies have investigated this and come to differing conclusions. We therefore aimed to investigate whether PDE5 inhibitor use is associated with an increased risk of malignant melanoma, and whether any increase in risk is likely to represent a causal relationship.

Then we jump down to the Conclusions section:

Our results were not consistent with PDE5 inhibitors being causally associated with melanoma risk, and strongly suggest that observed risk increases are driven by greater sun exposure among patients exposed to a PDE5 inhibitor.

We will continue to monitor both the legal and medical aspects of this still-emerging drug safety issue concerning Viagra, Cialis, Levitra, and similar drugs.

 

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review done by attorney Tom Lamb)