European Agency Warns of Toe Amputations Caused by Invokana, Farxiga and Xigduo

The European Medicines Agency (EMA) reported that a potential increased risk of lower limb amputation (mostly affecting the toes) exists in patients taking the SGLT2 inhibitors canagliflozin (Invokana), dapagliflozin (Farxiga and Xigduo) and empagliflozin (Jardiance) used for type 2 diabetes.

The review of SGLT2 inhibitors was prompted by an increase in lower limb amputations (mostly affecting the toes) in patients taking canagliflozin in two clinical trials, CANVAS and CANVAS-R. The studies, which are still ongoing, involved patients at high risk of heart problems and compared canagliflozin with placebo.

Some 230 lawsuits against the makers of Invokana are centralized before US District Judge Brian R. Martinotti in New Jersey in MDL 2750, IN RE: Invokana (Canagliflozin) Products Liability Litigation.

About 20 lawsuits against the makers of Farxiga are centralized before US District Judge Lorna G. Schofield in the Southern District of New York in MDL 2776, IN RE: Farxiga (Dapagliflozin) Products Liability Litigation.

The European Medicines Agency (EMA) is a decentralized agency of the European Union (EU), located in London. It began operating in 1995. The Agency is responsible for the scientific evaluation, supervision and safety monitoring of medicines developed by pharmaceutical companies for use in the EU.

Increased risk of toe amputation

All patients with diabetes (especially those with poorly controlled diabetes and problems with the heart and blood vessels) are at higher risk of infection and ulcers (sores) which can lead to amputations. The mechanism by which canagliflozin may increase the risk of amputation is still unclear.

An increase in lower limb amputations has not been seen in studies with other medicines in the same class, dapagliflozin and empagliflozin. However, data available to date are limited and the risk may also apply to these other medicines.

Further data are expected from ongoing studies with canagliflozin, dapagliflozin and empagliflozin.

A warning of the potential increased risk of toe amputation will be included in the prescribing information for these medicines. For canagliflozin, the prescribing information will also list lower limb amputation as an uncommon side effect (occurring in between 1 and 10 patients in 1,000). Doctors may consider stopping treatment with canagliflozin if patients develop significant foot complications such as infection or skin ulcers.

The review of SGLT2 inhibitors was carried out by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC recommendations have now been endorsed by the Committee for Medicinal Products for Human Use (CHMP), and will be sent to the European Commission for a final legally-binding decision valid throughout the EU.

Symptoms

  • The diabetes medicine canagliflozin may increase the risk of lower limb amputation (mostly affecting the toes).
  • The risk of lower limb amputation with canagliflozin may also apply to other diabetes medicines in the same class, dapagliflozin and empagliflozin.
  • All patients with diabetes are at increased risk of infection and sores which can lead to amputations. It is not known how canagliflozin may increase the risk of toe amputation.
  • If you are taking medicines containing canagliflozin, dapagliflozin and empagliflozin to treat your type 2 diabetes, it is particularly important that you check your feet regularly and follow your doctor’s advice on routine preventative foot care and adequate hydration.
  • Tell your doctor about any wounds or discoloration, or if your feet are tender or painful.
  • If you have any questions or concerns about your treatment, speak to your doctor, pharmacist or nurse.

SGLT2 Inhibitor and Diabetic Ketoacidosis

Invokana, Jardiance, Farxiga and other SGLT2 inhibitors are approved to lower blood sugar in patients with Type 2 diabetes. In May 2015, the FDA announced that it was investigating 20 reports of diabetic ketoacidosis that had occurred in people taking SGLT2 inhibitors. While some patients had been using the medications to treat Type 1 diabetes (an off-label use), a number of the ketoacidosis reports involved patients undergoing treatment for Type 2 diabetes. While ketoacidosis is often associated with Type 1 diabetes, it is unusual in patient with Type 2.

On December 4th, the FDA announced that new information about a potential association with diabetic ketoacidosis would be included on the labels for Invokana and other SGLT2 inhibitors. The alert indicated that from March 2013 to May 2015, the FDA had identified 73 cases of ketoacidosis in patients with Type 1 or Type 2 diabetes treated with SGLT2 inhibitors.

Diabetic ketoacidosis occurs when dangerous levels of toxic acids called ketone accumulate in the body. The condition can lead to hospitalization, diabetic coma and even death. “Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have any symptoms of ketoacidosis, a serious condition in which the body produces high levels of blood acids called ketones. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing,” the FDA said in its December 4th communication.

Patients who used Invokana or another SGLT2 inhbitor may be entitled to compensation if they were hospitalized with ketoacidosis while undergoing treatment.

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Federal Court Establishes MDL 2776 for Farxiga and Xigduo Diabetes Drugs

The Judicial Panel on Multidistrict Litigation established MDL No. 2776 in New York to hear claims of diabetic ketoacidosis and kidney damage caused by the Farxiga and Xigduo diabetes drugs.

The defendants in In Re: Farxiga (Dapagliflozin) Products Liability Litigation are Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals LP, AstraZeneca LP, AstraZeneca PLC, and AstraZeneca AB. There are 18 actions that involve allegations that ingestion of the drug Farxiga may cause a variety of injuries, including diabetic ketoacidosis and kidney damage.

The JPMDL assigned the cases to Judge Lorna G. Schofield of the Southern District of New York. She is already presiding over 13 constituent and tag-along actions pending in the district

Farxiga and its sister drug Xigduo XR belong to a class of diabetes drugs known as Sodium Glucose Cotransporter 1 2 (SGLT2) inhibitors. Other SLGT2 inhibitors include Invokana (canagliflozin) and Jardiance (empagliflozin). The actions share factual questions arising from allegations that taking Farxiga or Xigduo XR may result in patients suffering kidney-related injuries, such as diabetic ketoacidosis and kidney damage. The actions thus implicate many common issues concerning the development, manufacture, testing, regulatory history, promotion, and labeling of the drugs.

As a result of ingesting Farxiga, the plaintiffs have suffered sudden onset of life-threatening diabetic ketoacidosis (often in the setting of normal blood glucose levels), and/or acute renal failure, and/or pyelonephritis (kidney infection) and/or urosepsis and continue to suffer from the sequelae of these injuries. Farxiga (dapagliflozin) is a pharmaceutical drug used to treat Type 2 Diabetes. All of these injuries were the subject of recent FDA safety advisories.

On January 8, 2014, the FDA approved Farxiga for use in treatment of type 2 diabetics.2 Farxiga is a part of the gliflozin drug class. The gliflozin class is referred to generally as SGLT2 (short for “Sodium Glucose Cotransporter 2”) inhibitors. Xigduo XR was (dapagliflozin combined with metformin) designed and made by the same defendants as Farxiga, and is an extension of the Farxiga product line. Xigduo XR was approved shortly after Farxiga, on October 29, 2014.

FDA safety warning

On December 4, 2015 the FDA issued a safety communication disclosing they had found 73 adverse events reported between March 2013 and May 2015 that required hospitalization due to ketoacidosis-related to SGLT2 inhibitors. The FDA noted adverse event reports “include only reports submitted to FDA, so there are likely additional cases about which we are unaware.”

The same safety communication also warned of “life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis). In light of the data disclosed in the December 4, 2015 safety communication, the FDA changed the label for Farxiga and Xigduo XR to include a warning “about the risks of too much acid in the blood” and urged patients taking SGLT2 inhibitors to stop taking the drug and seek immediate medical attention if they have any symptoms of ketoacidosis. The FDA also required a label change to warn of urosepsis and pyelonephritis. On June 14, 2016, the FDA issued a safety announcement which advised that the existing warning about the risk of acute kidney injury on the Farxiga and Xigduo labels would be strengthened.

 

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Health Canada Warns of Diabetic Ketoacidosis from Invokana Diabetes Drug

invokana-warning kidney-damageHealth Canada, the country’s equivalent of the US Food and Drug Administration, warned healthcare professionals about the risk of diabetic ketoacidosis caused by SGLT2 Inhibitors, including Invokana, (canagliflozin), Farxiga (dapagliflozin), Xigduo (dapagliflozin/metformin), and Jardiance (empagliflozin).

The leading case is Arthur Portnoff V. Janssen Pharmaceuticals, Inc., Janssen Research and Development, LLC, Johnson & Johnson Co., and Mitsubishi Tanabe Pharma Corp., Case ID: 151200653, filed In the Philadelphia Court of Common Pleas. For more info read:

FDA strengthens kidney warnings for diabetes medicines Invokana, Invokamet, Farxiga and Xigduo XR

The warning was issued to healthcare professionals including internal medicine specialists, endocrinologists, cardiologists, nephrologists, general or family practitioners, emergency healthcare professionals, critical care physicians, certified diabetes educators and pharmacists.

Key messages

  • Serious, sometimes life-threatening and fatal cases of diabetic ketoacidosis (DKA) have been reported in patients on sodium glucose co-transporter 2 (SGLT2) inhibitors for type 1 and type 2 diabetes.
  • In a number of these cases, the presentation of the condition was atypical with only moderately increased blood glucose levels observed.
  • SGLT2 inhibitors are NOT indicated for the treatment of type 1 diabetes mellitus and should not be used in type 1 diabetes.
  • It is recommended that:
    • if DKA is suspected or diagnosed, treatment with SGLT2 inhibitors should be discontinued immediately.
    • SGLT2 inhibitors should not be used in patients with a history of DKA.
    • in clinical situations known to predispose to ketoacidosis (e.g. major surgical procedures, serious infections and acute serious illness), consideration be given to temporarily discontinuing SGLT2 inhibitor therapy.
    • patients be informed of the signs and symptoms of DKA and be advised to immediately seek medical attention if they develop them.
    • caution be used before initiating SGLT2 inhibitor treatment in patients with risk factors for DKA.

A life-threatening condition

Clinical trial and post-market cases of DKA, a serious, life-threatening condition requiring urgent hospitalization have been reported in patients with type 1 and type 2 diabetes mellitus on SGLT2 inhibitor treatment.

In a number of these reports, the presentation of the condition was atypical with only moderately increased blood glucose levels observed. Such atypical presentation of DKA in patients with diabetes could delay diagnosis and treatment.

Products affected
Brand Name Medicinal Ingredients Manufacturer
INVOKANA® canagliflozin Janssen Inc.
FARXIGA® dapagliflozin AstraZeneca Canada Inc.
XIGDUO® dapagliflozin and metformin AstraZeneca Canada Inc.
JARDIANCE empagliflozin Boehringer Ingelheim (Canada) Ltd.

Background information

Sodium glucose co-transporter type 2 (SGLT2) inhibitors are a class of drugs indicated as oral antihyperglycemic agents for the treatment of patients with type 2 diabetes.

The underlying mechanism for SGLT2 inhibitor-associated ketoacidosis is not clearly established. DKA usually develops when insulin levels are too low to prevent ketoacid accumulation. DKA occurs most commonly in patients with type 1 diabetes and is usually accompanied by high blood glucose levels (>14 mmol/L). However, the cases referred to above also concern patients with type 2 diabetes and in a number of cases blood glucose levels were only slightly increased, in contrast to typical cases of DKA.

The majority of the patients described in the above reports required hospitalization. To date, many of them have occurred during the first 2 months of treatment.  In many cases, just before or at the same time as the ketoacidosis occurred, patients experienced dehydration, low food intake, weight loss, infection, surgery, vomiting, a decrease in their insulin dose or poor control of diabetes.

A substantial proportion of the cases concerned use of SGLT2 inhibitors in patients with type 1 diabetes. SGLT2 inhibitors are NOT indicated for treatment of type 1 diabetes mellitus.

Who is affected

Information for consumers

Diabetic ketoacidosis (DKA) is a serious complication of diabetes caused by low insulin levels. Rare cases of this condition, including life-threatening and fatal ones, have occurred in patients taking SGLT2 inhibitors [INVOKANA®(canagliflozin), FORXIGA® (dapagliflozin), XIGDUO® (dapagliflozin/metformin), JARDIANCETM (empagliflozin)] for type 1 and type 2 diabetes.

A number of these cases have been unusual, with patients having blood sugar levels that are not as high as typically expected in DKA, which can lead to a delay in diagnosis and treatment.

Patients taking any of these medicines should be aware of the symptoms of DKA, including loss of appetite, nausea or vomiting, stomach pain, feeling very thirsty, rapid breathing, confusion, feeling unusual tiredness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odour to urine or sweat.

Patients should immediately seek medical advice if they develop any of these symptoms. Patients should also inform their healthcare professional about medical issues or factors (see below) that may predispose them to ketoacidosis.

SGLT2 inhibitors are NOT indicated for treatment of type 1 diabetes mellitus and should not be used in type 1 diabetes.

Information for health care professionals

Before initiating treatment with SGLT2 inhibitors, factors in the patient history that may predispose to ketoacidosis should be considered. These factors include:

  • patients on a very low carbohydrate diet (as the combination may further increase ketone body production),
  • an acute serious illness,
  • pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery),
  • sudden insulin dose reduction (including insulin pump failure),
  • alcohol abuse,
  • conditions that lead to severe dehydration,
  • hospitalization for major surgery or serious medical illness.

SGLT2 inhibitors should be used with caution in these patients. In addition, patients should be informed of these risk factors.

SGLT2 inhibitors should not be used in patients with a history of DKA.

A substantial proportion of the cases concerned off-label use in patients with type 1 diabetes. Prescribers are reminded that type 1 diabetes is NOT an approved indication for SGLT2 inhibitors.

Patients on SGLT2 inhibitors should be tested for ketones when they present with symptoms of acidosis in order to prevent delayed diagnosis and patient management.  If ketoacidosis is suspected, treatment with SGLT2 inhibitors should be discontinued.

Prescribers should inform patients of signs and symptoms of metabolic acidosis and advise them to immediately seek medical advice if they develop such signs and symptoms.

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FDA strengthens kidney warnings for diabetes medicines Invokana, Invokamet, Farxiga and Xigduo XR

invokana-warning kidney-damageThe U.S. Food and Drug Administration (FDA) has strengthened the existing warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). Based on recent reports, it has revised the warnings in the drug labels for these SGLT2 Inhibitors to include information about acute kidney injury and added recommendations to minimize this risk.

Patients should seek medical attention immediately if they experience signs and symptoms of acute kidney injury. This is a serious condition in which the kidneys suddenly stop working, causing dangerous levels of wastes to build up in the body. Signs and symptoms of acute kidney injury may include decreased urine or swelling in the legs or feet. Patients should not stop taking their medicine without first talking to their health care professionals. Doing so can lead to uncontrolled blood sugar levels that can be harmful.

Health care professionals should consider factors that may predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin. These include:

  • Decreased blood volume
  • Chronic kidney insufficiency
  • Congestive heart failure
  • Taking other medications such as:
    • diuretics
    • blood pressure medicines called angiotensin-converting enzyme (ACE) inhibitors
    • angiotensin receptor blockers (ARBs)

Canagliflozin and dapagliflozin are prescription medicines used with diet and exercise to help lower blood sugar in adults with type 2 diabetes. They belong to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Canagliflozin and dapagliflozin lower blood sugar by causing the kidneys to remove sugar from the body through the urine. Untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease.

101 cases of acute kidney injury

From March 2013, when canagliflozin was approved, to October 2015, FDA received reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use. This number includes only reports submitted to FDA, so there are likely additional cases about which the FDA is unaware. In approximately half of the cases, the events of acute kidney injury occurred within 1 month of starting the drug, and most patients improved after stopping it. Some cases occurred in patients who were younger than 65 years. Some patients were dehydrated, had low blood pressure, or were taking other medicines that can affect the kidneys.

The leading case is Arthur Portnoff V. Janssen Pharmaceuticals, Inc., Janssen Research and Development, LLC, Johnson & Johnson Co., and Mitsubishi Tanabe Pharma Corp., Case ID: 151200653, filed In the Philadelphia Court of Common Pleas.

Portnoff, of Beaumont, Texas, has taken the prescription drug Invokana, which is a member of the gliflozin class of pharmaceuticals, also known as sodium glucose co-transporter 2 (“SGLT2”) inhibitors. SGLT2 inhibitors inhibit renal glucose reabsorption through the SGLT2 receptor in the proximal renal tubules, causing glucose to be excreted through the urinary tract. This puts additional stress on the kidneys in patients already at risk for kidney disease.

While taking Invokana in Philadelphia, Pennsylvania, Portnoff developed diabetic ketoacidosis on or about February 20, 2015, as a result of treatment with Invokana, and was hospitalized at Hahnemann University Hospital in Philadelphia. As a result of his development of diabetic ketoacidosis, he  developed serious complications which required multiple days of hospitalization. Portnoff has endured pain and suffering, emotional distress, loss of enjoyment of life, and economic loss, including significant expenses for medical care and treatment which will continue in the future.

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Diabetes Drug Invokana Linked to Serious Side Effects Including Kidney Failure and Ketoacidosis

invokanaFDA Revises Invokana Warning Label

According to the Invokana Legal Help Center, the most serious side effect concerns related to the Type 2 diabetes drug Invokana and other SGLT-2 Inhibitors involve a potential increased risk of diabetic ketoacidosis (DKA), a serious medical condition characterized by too much acid in the blood, but there have also been growing concerns about the potential for Invokana to cause kidney failure side effects in users.

For individuals who have been adversely affected by kidney failure side effects of Invokana, it is recommended to consult a knowledgeable Invokana attorney today for legal help. Victims may be entitled to financial compensation for injuries and medical expenses, which can pursued by filing a product liability lawsuit against Invokana maker Johnson & Johnson and its JanssenPharmaceuticals unit.

Possible Invokana Side Effects

Invokana (canagliflozin) is a prescription drug designed to control blood sugar levels in adults with Type 2 diabetes, which it does by inhibiting a protein called sodium-glucose cotransporter-2 (SGLT2), thereby preventing the kidneys from reabsorbing glucose and causing them to excrete more glucose in the urine. However, there have been dozens of reports of potentially life-threatening complications occurring in patients taking Invokana and similar SGLT2 inhibitors, and researchers have advised healthcare professionals to exercise caution when prescribing the diabetes medication, due to the risk that Invokana may increase a patient’s chances of suffering diabetic ketoacidosis or kidney failure complications.

Because Invokana is designed to act on the kidneys to lower glucose levels, the medication poses serious risks for patients who have pre-existing kidney problems. Even diabetes itself can cause damage to the kidneys over time, and patients with late-stage diabetes who take a drug like Invokana may significantly increase their chances of suffering kidney failure. In its QuarterWatch report released in May 2015, the Institute for Safe Medication Practices (ISMP) indicated that Invokana was named in more than 457 adverse event reports submitted during the first year the drug was on the market, including 54 reports of kidney damage or kidney failure. This report came on the heels of a drug safety communication from the FDA warning about the alleged risk of diabetic ketoacidosisside effects from Invokana.

FDA Revises Invokana Warning Label

In another FDA safety announcement issued in December 2015, the FDA added new warnings to the labels of SGLT2 inhibitors like Invokana, indicating that the diabetes drugs may increase the risk of complications like ketoacidosis and serious urinary tract infections, both of which can result in hospitalization. According to the December 2015 safety announcement, the FDA had 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 […] from March 2013 to 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.”

An Experienced Invokana Lawyer Can Help

In light of these serious risks, the FDA is requiring the makers of Invokana and other SGLT2 inhibitors to conduct post-marketing research to identify reports of spontaneous diabetic ketoacidosis and other side effects in patients treated with the diabetes drugs. If you took an SGLT2 inhibitor like Invokana, and you have since been diagnosed with diabetic ketoacidosis, kidney failure or another serious medical condition, an experienced Invokana attorney can help. With a qualified lawyer on your side who has experience handling Invokana injury claims, you can ensure that your legal rights are protected, and seek fair and timely reimbursement for your injuries, past and future medical costs, and pain and suffering.

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