According to an FDA “Safety Alert,” issued in June 2016, the agency indicated that about five of every 1,000 patients taking a 300-milligram daily dose of canagliflozin-the active ingredient in Invokana and other Type 2 diabetes medicines-required amputations. Seven of every 1,000 patients taking a 100-milligram daily dose also required amputations.
Amputations involved toes, feet, and legs. Agency officials noted that they are looking into if canagliflozin elevates amputation risks. “Patients taking [canagliflozin] should notify their health care professionals right away if they notice any new pain or tenderness, sores or ulcers, or infections in their legs or feet,” the agency wrote.
The U.S. Food and Drug Administration (FDA) issued a “Safety Announcement” on May 15, 2015 over Type 2 diabetes medications known as sodium-glucose cotransporter-2 (SGLT2) inhibitors, also known as SGLT2 inhibitors. These drugs may lead to a serious condition known as ketoacidosis, which causes the body to produce high levels of blood acids known as ketones. Ketoacidosis may lead to severe reactions that may require hospitalization.
The personal injury attorneys at Parker Waichman LLP are investigating the association between SGLT2 Type 2 diabetes medications and heart attack, stroke, renal failure, diabetic ketoacidosis, or the need for amputations and are also investigating potential lawsuits. If you or someone you know suffered adverse reactions following treatment with these medications, our personal injury attorneys would like to hear from you.
SGLT2 Inhibitors: Invokana, Invokamet, Farxiga, Xigduo XR, Jardiance, Glyxambi
SGLT2 inhibitors received FDA approval for use in diabetes care and are prescribed along with improved nutrition, a low carbohydrate diet, and exercise to help control a patient’s diabetes by leading to lower blood sugar levels in adults diagnosed with Type 2 diabetes (diabetes mellitus).
Type 2 diabetes is typically associated with weight gain, an increased body mass index (BMI), glucose control issues, and an obese body type. Metabolic syndrome describes a cluster of conditions that includes increased blood pressure, high blood sugar level, excess body fat in the waist area, and abnormal cholesterol levels, all of which occur together and increase risks for serious diseases, including diabetes, stroke, and heart disease.
SGLT2 inhibitors lower blood sugar levels by causing the kidneys to remove sugar from the body and cause the blood sugar to be secreted in the urine.
SGLT2 inhibitors are prepared as single-ingredient and combination drugs, such as in combination with other diabetes drugs, including metformin. Canagliflozin is the only active ingredient in Invokana. Invokana with the active ingredient, metformin, is known as Invokamet.
SGLT2 inhibitors are not approved for the treatment of Type 1 diabetes. SGLT2 inhibitors are made with the following active ingredients: canagliflozin, dapagliflozin, and empagliflozin. The Type 2 diabetes drugs are sold by AstraZeneca, Johnson & Johnson, and Eli Lilly in partnership with Boehringer Ingleheim and are sold in the following combinations and brand names:
- Invokana: canagliflozin (Johnson & Johnson)
- Invokamet: canagliflozin and metformin
- Farxiga: dapagliflozin (AstraZeneca)
- Xigduo XR: dapagliflozin and metformin extended-release
- Jardiance: empagliflozin (Lilly and Boehringer)
- Glyxambi: empagliflozin and linagliptin
FDA Increases Warnings on Janssen Pharmaceuticals’ Invokana, Invokamet and Kidney Damage
Effective June 2018, the FDA strengthened the existing warning about the risk of acute kidney injury for the Type 2 diabetes medicines Invokana and Invokamet (canagliflozin) and Farxiga, and Xigduo XR (dapagliflozin). Recent reports led to the revised warnings on the drugs’ labeling, according to the FDA, and now include information about acute kidney injury, as well as additional recommendations to minimize this risk.
The FDA has received 101 confirmable cases of acute kidney injury which, in some cases, involved hospitalization and dialysis this from March 2013, when Invokana and Invokamet were approved, to October 2015. This amount only involves those reports submitted to the FDA; therefore, according to federal regulators, there are likely more cases about which the agency is not aware.
More than half of the cases of acute kidney injury-a total of 58 percent-occurred within one month after the patient began taking the diabetes drug, wrote Law360. Some cases occurred in patients who were younger than 65 years of age and some were dehydrated, suffered from low blood pressure, or were taking other medicines that can affect the kidneys, according to the FDA.
The agency recommends that health care professionals consider those factors that may predispose patients to acute kidney injury before prescribing them Invokana, Invokamet, Farxiga, and Xigfuo XR. Such factors include, “decreased blood volume; chronic kidney insufficiency; congestive heart failure”; as well as taking other drugs “that may increase the risk through interaction, “such as diuretics, blood pressure medicines known as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); and nonsteroidal anti-inflammatory drugs (NSAIDs). Physicians should assess patient kidney function prior to starting these medications and should continue with periodic monitoring. Should acute kidney injury occur, the FDA advises prompt discontinuation of the medication and treat the kidney impairment. Patients should also seek immediate medical attention should they experience symptoms of acute kidney injury (see symptom list below), a serious condition in which the kidneys suddenly stop working. This may lead to dangerous levels of wastes building in the body. Patients should not stop taking their medicine without first talking to their health care professionals as this may lead to uncontrolled blood sugar levels that may be harmful.
FDA Warns that Janssen Pharmaceuticals’ Invokana, Invokamet Linked to Amputations in Clinical Trial
On May 18, 2016, the FDA issued a “Drug Safety Communication” warning that the diabetes medicine canagliflozin may be linked to a higher risk of leg and foot amputations. The alert was based on the interim safety results of an ongoing clinical trial. Canagliflozin is sold under the brand names Invokana (canagliflozin) and Invokamet (canagliflozin and metformin) and is manufactured by Janssen Pharmaceuticals, a unit of the healthcare giant, Johnson & Johnson.
According to the interim data, patients were twice as likely to suffer amputations while using Invokana and Invokamet compared to patients taking a placebo. The FDA alert states that the risk equated to five of every 1,000 patients taking a 300-milligrams daily. In patients taking a 100-milligram daily dose, the risk equated to seven of every 1,000 patients. Patients suffered amputations of the toes, feet, and legs.
The FDA indicated that it was working to further investigate the link between canagliflozin and the occurrence of an amputation. Patients were advised against stopping their medication without consulting their physicians first. “Patients taking [canagliflozin] should notify their health care professionals right away if they notice any new pain or tenderness, sores or ulcers, or infections in their legs or feet,” the FDA wrote.
The FDA approved canagliflozin in March 2013 to treat patients with Type 2 diabetes. Along with its approval, FDA mandated several post-marketing studies to evaluate the risk of certain adverse events, including:
- Cardiovascular events
- Severe hypersensitivity reactions
- Photosensitivity reactions
- Liver abnormalities
- Adverse pregnancy outcomes
- Bone safety
Additionally, the FDA required two pediatric studies under the Pediatric Research Equity Act (PREA) to evaluate whether Invokana/Invokamet is safe and effective in children. Based on trial findings, the FDA warned of increased risk of bone fracture associated with canagliflozin in 2015.
FDA Strengthens Warning on Invokana and Invokamet Due to Bone Fracture Risk
In September 2015, the FDA strengthened the warning on Invokana (canagliflozin) and Invokamet
(canagliflozin and metformin), Type 2 diabetes drugs in the SGLT2 class, to include information about the increased risk of bone fractures. The agency also added additional information about reduced bone mineral density. In light of this information, the FDA advises health care professionals to consider whether patients are already at increased risk for bone fractures before prescribing Invokana or Invokamet.
The warning label indicates that bone fractures have been reported in patients taking canagliflozin, occurring as early as 12 weeks after starting treatment. Invokana has been linked to reduced bone mineral density at the hip and lower spine.
Health care professionals should discuss risk factors for bone fractures, the FDA notes. The agency also indicated that it, “is continuing to evaluate the risk of bone fractures with other drugs in the SGLT2 inhibitor class,” including Farxiga and Xigduo XR (dapagliflozin) and Jardiance, Glyxambi, and Synjardy (empaglifozin), to determine if additional label changes or studies are needed.
Ketoacidosis and Other Possible Side Effects of SGLT2 Inhibitors
Acidosis occurs when there is an excess of acid in the body. Ketoacidosis associated with SGLT2 inhibitors may be present even if the blood sugar is not very high. The agency advises patients to be aware of the signs of ketoacidosis, a serious side effect, and to seek immediate medical attention if any of these symptoms occur:
- Difficulty breathing
- Abdominal pain
- Unusual fatigue or sleepiness.
In addition to ketoacidosis, SGLT2 inhibitors may also lead to the following potential side effects:
- Kidney problems
- Low blood sugar (when this class of medicines is combined with other prescription medicines used to treat diabetes)
- Increased blood cholesterol
- Yeast infections.
The FDA Adverse Event Reporting System (FAERS) database identified 20 cases of acidosis from March 2013 to June 6, 2014 that were reported as diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients who were being treated with SGLT2 inhibitors.
The FDA indicates that, since June 2014, it has received additional FAERS reports for DKA and ketoacidosis in patients receiving treatment with SGLT2 inhibitors. DKA is considered a sub-set of ketoacidosis or ketosis in patients diagnosed with diabetes and is a type of acidosis that typically occurs when insulin levels are too low or during periods of prolonged fasting. DKA is usually seen in patients diagnosed with Type 1 diabetes and is most typically associated with high blood sugar levels.
According to the FDA, the FAERS cases reported are not typical for DKA as most of the patients involved were diagnosed with Type 2 diabetes and their blood sugar levels, when reported, were only slightly increased when compared to typical DKA cases. In every case, a diagnosis of DKA or ketoacidosis was made by a health care professional and hospitalization was required. A temporal (time-based) tie with SGLT2 inhibitor initiation was seen in every case with a median onset time of an average of two weeks; however, the range was anywhere from one to 175 days).
According to the agency, post-marketing cases reveal an association between sodium-glucose cotransporter-2 (SGLT2) inhibitor use and the development of a high anion gap metabolic acidosis with elevated urine or serum ketones and was not associated with the very high glucose levels that are normally seen in diabetic ketoacidosis. In other words, it appeared as if the SGLT2 inhibitor drug was associated with the acidosis.
Complications of Diabetic Ketoacidosis without prompt and appropriate treatment, DKA complications may occur and include:
- Cerebral edema (swelling of the brain)
- Acute kidney failure
- Adult respiratory distress syndrome
- Heart Attack
Cerebral edemaBrain swelling occurs when too much water accumulates in the brain. Cerebral edema is seen in one of every 150 cases of diabetic ketoacidosis; one in four cases may be fatal. The condition is serious, typically requires intensive care unit (ICU) treatment in a hospital, and may lead to severe brain damage. The reason for the water build-up remains unknown. Symptoms include:
Acute Kidney FailureSevere dehydration may lead to acute kidney failure, which may lead to the following symptoms and may require dialysis to filter waste products from the blood until the dehydration is resolved and the kidneys begin working properly:
- Decreased urine
- Edema (swelling) in the arms, legs, and/or feet
- Feeling tired
Adult Respiratory Distress SyndromeDiabetic ketoacidosis may lead to fluid level changes that may be both rapid and unpredictable and may lead to the lungs becoming filled with fluid. This condition is known as adult respiratory distress syndrome and may lead to significant breathing difficulties. Treatment typically involves assistance with a ventilator until the condition stabilizes.
Legal Help for Victims of the SGLT2 inhibitor-Related DKA, Stroke, Heart Attack, or Renal Failure
If you or someone you know suffered adverse reactions including DKA, Stroke, Heart Attack, Renal Failure, or amputation following use of a SGLT2 Type 2 diabetes drug, you may have valuable legal rights, including filing a Ketoacidosis lawsuit. For a free lawsuit evaluation with a personal injury attorney, please fill complete our online form or call 1-800-YOURLAWYER (1-800-968-7529) today.