Drug Injury Watch

FDA Mandates Label Change Warning About Fatal Cases Of Ketoacidosis For All Diabetes Drugs Known As Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors

This Class Of (Heavily Advertised) Drugs Includes Farxiga, Invokana, And Jardiance, Which Also Are Linked To Kidney Failure And Heart Attacks Or Myocardial Infarction

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In an earlier article, "Summer 2016 Update On Diabetes Medicines Invokana / Farxiga / Jardiance: Drug Label Changes And Safety Investigations", we pointed out that Jardiance (empagliflozin), Glyxambi (empagliflozin and linagliptin), and Synjardy (empagliflozin and metformin hydrochloride) had a July 2016 label change for fatal cases of ketoacidosis, but several other diabetes drugs are known as Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors did not have a similar label change.

It turns out that this was only a matter of time, or timing. In August 2016 we saw FDA letters about approving and mandating a label change for ketoacidosis cases go out for the remaining diabetes medicines in this SGLT2 inhibitors class of drugs: Invokana (canagliflozin); Invokamet (canagliflozin and metformin); Farxiga (dapagliflozin); and, Xigduo XR (dapagliflozin and metformin extended-release).

For use as an example, here is the relevant part of an August 17, 2016 FDA Supplemental Approval letter to AstraZeneca Pharmaceuticals LP for Farxiga:

Please refer to your supplemental New Drug Application (sNDA) dated and received July 28 2016, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Farxiga (dapagliflozin) tablets.

We also refer to our letter dated July 8, 2016, notifying you, under Section 505(o)(4) of the FDCA, of new safety information that we believe should be included in the labeling for sodiumglucose cotransporter-2 (SGLT-2) inhibitors. This information pertains to the risk of fatal ketoacidosis.

The letter showed as Enclosure the Content of Labeling, which was not immediately available on the FDA's website on August 17 for review. But today we found the Farxiga "Revised 8/2016" Prescribing Information document -- which is commonly called the "drug label" by most people -- by using the DailyMed website (U.S. NATIONAL LIBRARY OF MEDICINE).

Here is the new ketoacidosis side effect warning from this revised Farxiga drug label:

5.2 Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including FARXIGA. Fatal cases of ketoacidosis have been reported in patients taking FARXIGA. FARXIGA is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1.1)].

Patients treated with FARXIGA who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with FARXIGA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, FARXIGA should be discontinued, the patient should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating FARXIGA, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction and alcohol abuse. In patients treated with FARXIGA consider monitoring for ketoacidosis and temporarily discontinuing FARXIGA in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

 

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Invokana / Farxiga / Jardiance

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Besides ketoacidosis there are other serious side effects associated with Farxiga, Invokana, Jardiance, and the several other diabetes medicines in this SGLT2 inhibitors class of drugs:

• Acute Kidney Injury
• Kidney Failure / Renal Failure
• Kidney Damage
• Pyelonephritis (kidney infection)
• Urosepsis (blood infection)
• Urinary Tract Infection (UTI)
• Heart Attacks / Myocardial Infarctions (MI)
• Ischemic Stroke / Cerebral Vascular Accident (CVA)
• Deep Vein Thrombosis (DVT)
• Pulmonary Embolism (PE)

We are currently investigating possible drug injury lawsuits against the responsible pharmaceutical companies for diabetes patients who have developed ketoacidois or any of the other medical conditions listed above while using Invokana, Farxiga, Jardiance, Invokamet, Xigduo, Glyxambi, or Synjardy. 

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) 

Xarelto / Savaysa / Eliquis: Antidote Drug AndexXa Is Rejected By FDA In August 2016, Surprising Many Pharma Industry Observers (And Doctors?)

Portola, Which Developed AndexXa, Estimates 100,000 Patients Per Year Suffer From Severe Uncontrollable Bleeding Events That Could Require Such An Antidote

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In mid-August 2016 the US FDA rejected Portola Pharmaceutical's application to market AndexXa (andexanet alfa) as an antidote to three direct Factor Xa inhibitors:

• Eliquis (apixaban) from Pfizer/Bristol-Myers Squibb;
• Xarelto (rivaroxaban) from Bayer/Johnson & Johnson; and,
• Savaysa (edoxaban) from Daiichi Sankyo.

The reason this FDA rejection of the AndexXa application is remarkable:  There is no reversal agent for Factor Xa inhibitors approved in the United States.  

And these Factor Xa inhibitors, which serve as blood-thinner drugs, are being used by an increasing number of patients for stroke prevention and for treatment of deep vein thrombosis and pulmonary embolism.

From this August 18, 2016 article, "Is It "Game Over" After Portola's FDA Rejection?", posted on The Motley Fool website, we get this contextual information:

Portola Pharmaceuticals developed AndexXa to reverse the anticoagulant effects of a new and fast-growing class of drugs known as factor Xa inhibitors....

Factor Xa inhibitors' advantages have turned Xarelto and Eliquis into multibillion-dollar-per-year blockbusters already. But the absence of an antidote that can reverse their anticoagulant effects has kept factor Xa inhibitors from being used in sickly and frail patients, which has limited the peak sales potential of this class of medicine.

To overcome that headwind and broaden the use of their drugs, Johnson & Johnson, Bristol-Myers Squibb, and Pfizer provided funding to Portola Pharmaceuticals so it could develop AndexXa. Until now, that's appeared to be money well spent, because clinical trials have proven AndexXa reverses the effects of both Xarelto and Eliquis....

Because of the big unmet need for an antidote to factor Xa drugs, the FDA awarded AndexXa breakthrough status and agreed to an accelerated review of AndexXa's filing. Portola Pharmaceuticals estimates that up to 100,000 factor Xa patients per year suffer from emergency events that could require a factor Xa antidote.

 

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 Eliquis  ---  Savaysa  ---  Xarelto

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For some reporting on the unexpected FDA denial of this AndexXa application, we turn to this August 18, 2016 article, "FDA rejects reversal agent for anticoagulation drugs", from Healio CardiologyToday:

Portola Pharmaceuticals announced it received a complete response letter from the FDA that its reversal agent for Factor Xa inhibitor anticoagulants will not be approved at this time.

The agent, andexanet alfa (AndexXa), was developed for reversal of uncontrolled bleeding in patients treated with direct Factor Xa inhibitors such as apixaban (Eliquis, Bristol Myers-Squibb/Pfizer), edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen Pharmaceuticals) and indirect Factor Xa inhibitors such as enoxaparin, according to a press release issued by the company. Factor Xa inhibitors are often used for stroke prevention in patients with nonvalvular atrial fibrillation and for treatment of deep vein thrombosis and pulmonary embolism.

There is no reversal agent for Factor Xa inhibitors approved in the United States; the FDA in 2013 designated andexanet alfa as a breakthrough therapy and in 2015 designated it as an orphan drug, both enabling expedited review....

“Because AndexXa addresses an urgent unmet medical need, we and the FDA are committed to resolving the outstanding questions to determine the appropriate next steps,” Bill Lis, CEO of Portola, said in the release. “We plan to meet with the FDA as soon as possible.”

We have previously written about the safety problems presented by the fact that there is currently no FDA-approved antidote or reversal agent for Eliquis, Savaysa, and Xarelto:

• Eliquis, Savaysa, And Xarelto Worry Doctors Because No Antidote, Still
• Eliquis Might Be Safer Than Xarelto, But Neither Has Approved Antidote
• No Antidotes For Eliquis, Savaysa, And Xarelto To Stop Acute Bleeding
• Eliquis Antidote Will Come Too Late For People Who Suffered Serious Bleeding Events, Some Which Caused The Deaths Of Patients
• Because No Antidote For Eliquis Is Available To Reverse The Effects Of Anticoagulation, There Have Been Irreversible Life-Threatening And Fatal Bleeding Events
• Eliquis And Xarelto, Like Pradaxa, Linked To Serious Bleeding Events Due To Fact No Antidote Available

At the present time it is unknown when Portola will be in a position to resubmit its AndexXa application to the FDA, much less when the FDA will make its next determination about AndexXa being approved, or not.   

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) 

Denosumab Drugs Prolia And Xgeva Linked To QT Interval Prolongation Associated With Hypocalcemia

Australia's Drug Regulator Issues Warnings And Mandates Label Changes, Following Similar Action In Europe; Will FDA Follow Thess Leads?

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In early August 2016 we learned about some new apparent side effects of Prolia as well as Xgeva, QT interval prolongation and severe symptomatic hypocalcemia.

Denosumab is the active ingredient for Prolia and Xgeva, both of which are made by biotech pharmaceutical company Amgen Inc. Prolia is a treatment for osteoporosis and osteopenia. Xgeva is a drug used for the prevention of skeletal-related events in adults with bone metastases from solid tumors. 

This emerging drug safety issue was recently addressed by Australia’s Therapeutic Goods Administration (TGA), and was initially identified by that drug regulator during an assessment of adverse event reports relating to Prolia and Xgeva.

From this August 12, 2016 article, "Australia’s TGA issues warning on denosumab and QT prolongation", published on the ThePharmaLetter (subscription required) website, we get this detailed information:

Product information update

Hypocalcemia is a known effect of denosumab and was already captured in the Product Information (link is external) (PI).   However, there was previously no reference to QT prolongation, which is a potentially life-threatening disorder, or to severe symptomatic hypocalcemia.

The following sections of the PI have been updated:

• Precautions
  • in the post-marketing setting, severe symptomatic hypocalcemia has been reported, with most cases occurring in the first weeks of initiating therapy (although it can occur later);
  • routine clinical monitoring of calcium levels is recommended; and
  • information about the symptoms of hypocalcemia and the importance of maintaining calcium levels should be given to all patients being treated with denosumab.
• Adverse Effects
  • examples of the clinical manifestations of severe symptomatic hypocalcemia have included QT interval prolongation, tetany, seizures and altered mental status; and
  • symptoms of hypocalcemia in denosumab clinical studies included paresthesias or muscle stiffness, twitching, spasms and muscle cramps.

This updated information has harmonized the Australian PIs with the European Union Summary of Product Characteristics for these products.

We will watch for further developments concerning these emerging drug safety issues with Prolia and Xgeva, such as any similar regulatory action by the FDA here in the US.

 

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 Drug Injury Lawsuits Report: Diabetes Medicines, Erectile Dysfunction Pills, And Heartburn Medications

Current Product Liability Litigation Cases Involving Popular Drugs With Serious Side Effects That Are Starting To Gain More Attention

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

This article will feature three types of drug injury cases that are starting to gain some momentum in terms of the number of lawsuits filed against the responsible pharmaceutical companies in courts across the country.

(1) Diabetes Medicines in the Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors Class of Drugs

Invokana (canagliflozin) — Janssen Pharmaceuticals
Invokamet (canagliflozin and metformin) — Janssen Pharmaceuticals
Farxiga (dapagliflozin) — AstraZeneca Pharmaceuticals
Xigduo XR (dapagliflozin and metformin extended-release) — AstraZeneca Pharmaceuticals
Jardiance (empagliflozin) — Boehringer Ingelheim Pharmaceuticals
Glyxambi (empagliflozin and linagliptin) — Boehringer Ingelheim Pharmaceuticals
Synjardy (empagliflozin and metformin hydrochloride) — Boehringer Ingelheim Pharmaceuticals and Eli Lilly and Company

These drug injury lawsuits primarily involve the following side effects:

• Diabetic Ketoacidosis (DKA)
• Ketoacidosis
• Ketosis
• Acute Kidney Injury
• Kidney Failure / Renal Failure
• Kidney Damage
• Pyelonephritis (kidney infection)
• Urosepsis (blood infection)
• Urinary Tract Infection (UTI)

(2) Erectile Dysfunction (ED) Pills, Benign Prostatic Hyperplasia (BPH) Medicines, and Pulmonary Arterial Hypertension (PAH) Medications in the Phosphodiesterase 5 (PDE-5) Inhibitors Class of Drugs

Adcirca (tadalafil) -- Eli Lilly and Company
Cialis (tadalafil) -- Eli Lilly and Company
Levitra (vardenafil hydrochloride) -- GlaxoSmithKline
Revatio (sildenafil citrate) -- Pfizer
Staxyn (vardenafil hydrochloride) -- GlaxoSmithKline
Stendra (avanafil) -- Vivus and Auxilium Pharmaceuticals
Viagra (sildenafil citrate) -- Pfizer

These various prescription drug products have been linked to malignant melanoma skin cancer (but not basal or squamous cell skin cancers).

(3) Heartburn Medicines and Acid Reflux Pills like Prevacid, Prilosec, and Nexium in the Proton Pump Inhibitors (PPIs) Class of Drugs

Nexium (esomeprazole magnesium) [prescription drug] == AstraZeneca LP
Nexium 24HR (esomeprazole magnesium) [over-the-counter] -- Pfizer Consumer Healthcare
Prilosec (omeprazole) [prescription drug] -- AstraZeneca LP
Prilosec OTC (omeprazole) [over-the-counter] -- Procter & Gamble Manufacturing Co.
Prevacid (lansoprazole) [prescription drug] -- Takeda Pharmaceuticals America, Inc.
Prevacid 24 HR (lansoprazole) [over-the-counter] -- Novartis Consumer Health, Inc.

The use of these proton pump inhibitors (PPIs) for as little as a couple of weeks can result in an increased risk of developing:

• Acute Interstitial Nephritis (AIN)
• Chronic Kidney Disease (CKD)
• End-Stage Renal Disease (ESRD)
• Severe Renal Impairment
• Kidney / Renal Failure
• Acute Kidney Injury
  
  

We are currently investigating possible drug injury lawsuits against the responsible pharmaceutical companies for patients using these drugs who have developed the side effects listed above.

For more information, see these web pages at our Drug Injury Law: Medical & Legal Information site:

Invokana / Farxiga / Jardiance / Invokamet / Xigduo / Glyxambi / Synjardy

Viagra / Cialis / Levitra / Staxyn / Stendra / Revatio / Adcirca

Nexium / Prilosec / Prevacid

We have been representing patients and their family in drug injury lawsuits for the past 16 years and this is our main practice area.  Let us know if we can help you.

 

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)