Drug Injury Watch

New FDA Warning That Januvia, Onglyza, Tradjenta, And Nesina Are Associated With "joint pain that can be severe and disabling"

Label Changes About Side Effects For These Type 2 Diabetes Medicines In The Drug Class Called Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In August 2015 the FDA announced that it has found indications of a new side effect for a class of diabetes drugs -- dipeptidyl peptidase-4 (DPP-4) inhibitors -- that includes Januvia, Onglyza, Tradjenta, and Nesina.

The FDA found drug adverse event reports of arthralgia, or severe pain in one or more joints, associated with the use of DPP-4 inhibitor diabetes drugs, with Januvia being the one implicated most often, followed by Onglyza.

According to the FDA, patients started having symptoms of the new side effect from one day to years after they started taking Januvia, Onglyza, Tradjenta, Nesina or one of the "combination" DPP-4 inhibitors, e.g., Janumet (sitagliptin and metformin).

In more detail, the FDA reported that after the DPP-4 inhibitor medicine was discontinued, the patients' symptoms were usually relieved within less than a month of stopping the subject drug. Furthermore, some patients developed severe joint pain again when they restarted the same medicine or another DPP-4 inhibitor. 

This last fact provides some substantiation for linking this severe joint pain side effect with Januvia, Onglyza, Tradjenta, Nesina, and the other drugs in this DPP-4 inhibitors class.

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We get the following more detailed information from the "FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain" document that was issued on August 28, 2015:

In a search of the FDA Adverse Event Reporting System (FAERS) database, we identified 33 cases of severe arthralgia reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors from October 16, 2006, approval date of the first DPP-4 inhibitor, through December 31, 2013. Each case involved the use of one or more DPP-4 inhibitor. [Januvia (sitagliptin)] (n=28) was the most frequently reported, followed by [Onglyza (saxagliptin)] (n=5), [Tradjenta (linagliptin)] (n=2), [Nesina (alogliptin)] (n=1), and vildagliptin (n=2); vildagliptin is not marketed in the United States. In five cases, the patient experienced severe arthralgia with two different DPP-4 inhibitors. All 33 patients experienced arthralgia that resulted in a substantial reduction in their prior level of activity, including 10 patients who were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of initiation of treatment with a DPP-4 inhibitor. In 20 of the 33 cases, the DPP-4 inhibitor was suspected as a possible cause of arthralgia and was discontinued within a month following the onset of symptoms. However, 8 of the remaining 13 cases reported a period of 44 days to 1 year between the onset of symptoms and discontinuation of the DPP-4 inhibitor. In 23 of the 33 cases, symptoms resolved less than 1 month after discontinuation of the drug.

Reports of eight of the 33 cases documented a positive rechallenge. In these eight cases, individuals discontinued treatment, experienced a resolution of symptoms, restarted therapy with a DPP-4 inhibitor (a different member of the class in six of the eight cases), experienced the reappearance of the arthralgia, and subsequently, experienced resolution of the symptoms when DPP-4 inhibitor therapy was again discontinued. Twenty-one of the 33 patients were treated for arthritis with drug therapies that included corticosteroids, nonsteroidal anti-inflammatory drugs, methotrexate, and immune-modulating drugs....

We also searched the medical literature and identified seven case reports, two of which were also identified in the FAERS database....  [footnotes omitted]

Due to this drug safety development, the FDA has mandated that the respective drug companies add a new Warning and Precaution about this risk to the drug labels of all medicines in this dipeptidyl peptidase-4 (DPP-4) inhibitors class.

Here is a list of those drugs, which was included in this August 2015 FDA Drug Safety Communication:

Januvia -- sitagliptin
Janumet -- sitagliptin and metformin
Janumet XR -- sitagliptin and metformin extended release
Onglyza -- saxagliptin
Kombiglyze XR -- saxagliptin and metformin extended release
Tradjenta -- linagliptin
Glyxambi -- linagliptin and empagliflozin
Jentadueto -- linagliptin and metformin
Nesina -- alogliptin
Kazano -- alogliptin and metformin
Oseni -- alogliptin and pioglitazone

We will continue to monitor this emerging drug safety issue concerning reports of arthralgia, or severe pain in one or more joints, associated with the use of these newer diabetes drugs.

 

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

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In The Shadow Of Recent Announcement About Diabetes Drug Jardiance Medical Study Results There Lingers Safety Concerns For SGLT-2 Inhibitors

As With Invokana and Farxiga, Jardiance Is Subject Of Several Drug Regulatory Agency Investigations About Ketoacidosis And Other Side Effects

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

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UPDATE: "Health Canada Warns About Link Between DKA & Popular Diabetes Drugs"

(5/19/16)

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Jardiance is part of the Sodium-Glucose Co-Transporter-2 (SGLT-2) Inhibitors class of diabetes drugs, which also includes Invokana and Farxiga. 

These new SGLT-2 diabetes medications -- which are distinctive from other diabetes drugs insofar that they make the kidneys extract a significant amount of sugar from the blood to be excreted in urine -- are prescribed to treat Type-2 diabetes.

Unfortunately, over the years Type 2 diabetes has become much more common, in part due to the so-called obesity epidemic here in the US. About 95 percent of the nearly 30 million American adults and children -- which is almost 10 percent of the current US population -- have Type 2 diabetes. And approximately 86 million more Americans have been diagnosed with "pre-diabetes", with most of those individuals likely to develop diabetes in the future.

As such, the financial analysts who focus on the pharmaceutical sector were all abuzz earlier this week as regards an announcement about a new medical study concerning Jardiance.

From an August 20, 2015 Forbes article, "Sweet Victory: Eli Lilly's Jardiance Is First Diabetes Drug To Reduce Heart Attacks And Strokes", by reporter Matthew Herper, we get a sense of that excitement:

A big win for Eli Lilly this morning. Its diabetes drug Jardiance, co-marketed with Boehringer Ingelheim,  is the first blood-sugar lowering pill ever to reduce the risk of heart attacks, strokes, and cardiovascular deaths in a big study, according to a press release issued this morning.

Of course, we need to wait to see full details from the study, not just the press release Lilly and Boehringer issued this morning....

And that Forbes article continued with some discussion about the diabetes drugs market share implications of this recent drug company announcement about Jardiance.

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We get some additional information about the significance this new Jardiance medical study from this Associated Press (AP) news report, "Diabetes drug may protect against heart attack, stroke":

... [T]he drug's two manufacturers - Eli Lilly and Co. of Indianapolis and German partner Boehringer Ingelheim GmbH - have announced only that a three-year study they conducted showed the drug delayed the time until patients died of cardiovascular disease or suffered a heart attack or stroke.

That brief summary, known as the top-line result, is meant to inform investors promptly that the closely watched study met its main goal, a result likely to affect Eli Lilly's financial prospects and stock price....

Dr. Ananda Basu, a diabetes specialist at the Mayo Clinic, cautioned that it's impossible to predict how patient treatment will be affected until details of the study design, the size of Jardiance's benefits and any side effects are disclosed.

The two drugmakers plan to release detailed findings at [the European Association for the Study of Diabetes on September 17] and simultaneously publish them in a medical journal.

However, despite this glory-moment for Eli Lilly and Boehringer, all is not well for Jardiance as well as the other SGLT-2 inhibitors such as Invokana and Farxiga.

This situation becomes apparent by the titles of these earlier articles:

Farxiga / Jardiance / Invokana Safety As Regards Diabetic Ketoacidosis Now Being Studied By Health Canada In Addition To Current FDA Investigation

Invokana / Farxiga / Jardiance: New Medical Study Finds A History Of Diabetic Ketoacidosis Events Is Associated With Increased Risk of Death

May 2015 Diabetes Drugs – Ketoacidosis Link Warning By FDA Covers Invokana, Farxiga, And Jardiance, With Label Changes Possible

Accordingly, referring back to the AP news report above, we are anxious to see the September 2015 medical journal article which will have more details about this recent Jardiance study, and possibly some discussion about the side-effects risks associated with Jardiance.

 

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New Anti-Clotting Drug Savaysa Can Be Dangerous As It Has No Treatment Approved To Reverse The Anti-Coagulant Effect In Cases Of Bleeding

Like Eliquis, Xarelto, And Pradaxa, This New Blood-Thinner Is Being Sold By Drug Companies At A Time When Profits May Be Taking Priority Over Patient Safety

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Savaysa (edoxaban) is from the drug company Daiichi Sankyo, Inc.

Savaysa is the fourth new oral anticoagulant (NOAC) that has been brought to the US market in recent years before any so-called "antidote" was approved by FDA -- like Pradaxa, Xarelto, and Eliquis.

In a January 2015 FDA News Release that significant drug-safety issue was acknowledged.  From this item,  "FDA approves anti-clotting drug Savaysa", we get the following relevant information:

The U.S. Food and Drug Administration today approved the anti-clotting drug Savaysa (edoxaban tablets) to reduce the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem....

The most common side effects observed in clinical trial participants were bleeding and anemia. As with other FDA-approved anti-clotting drugs, bleeding, including life-threatening bleeding, is the most serious risk with Savaysa. There is no treatment that has been proven to reverse the anti-coagulant effect of Savaysa...  [emphasis added]

We have written several articles over the past year about the irreversible bleeding "side effect" of this new class of blood-thinning drugs in the context of Eliquis, as seen here:

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

More recently there was a Milwaukee Journal Sentinel / MedPage Today investigation which resulted in this news report by John Fauber and Coulter Jones, "New anticoagulant drugs provide stroke prevention with dose of danger".

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From that in-depth examination of this serious safety issue -- which is, unfortunately, mostly unknown by patients until it is literally too late -- we get this information:

Xarelto is one of four anticoagulants approved since 2010 that make up a class of drugs known as novel (or newer) oral anticoagulants, NOACS (pronounced No-aks) for short. Widely promoted as more convenient than warfarin, the drugs came to market with much fanfare anticipating blockbuster status.

But unlike warfarin, which is a vitamin K antagonist that can be turned off in a bleeding emergency or prior to surgery by administering vitamin K, all of the NOACs were approved without an antidote, although packed red blood cells can slow their anticoagulation action....

And later in that same investigative report we get these disturbing facts:

Concerns about the new drugs causing bleeding that could not be stopped have been raised for years:

■  In a 2011 letter to the New England Journal of Medicine, doctors in Houston warned about trauma patients using Pradaxa who had poor outcomes because of excessive bleeding. They described one patient who fell and died a short time later.

■  In a 2012 letter in the Journal of Neurosurgery, doctors in Salt Lake City warned of a similar case involving an elderly man who fell and suffered a brain hemorrhage.

■  In a 2014 paper in a hematology journal, doctors in Detroit reported a case of a 39-year-old woman who developed severe vaginal bleeding while on Xarelto. The bleeding eventually was stopped, but the doctors warned: "With the ever increasing number of patients using these new oral anticoagulants, the frequency of acute bleeds similar to our case encountered by physicians will continue to rise."

Now, with Savaysa starting to get some market share in the US, we expect to hear about Savaysa-related injury and death cases which involve people who had excessive bleeding, some who bled to death.  And, again, this is because Savaysa -- like Pradaxa, Xarelto, and Eliquis -- does not have an FDA-approved antidote, yet, for a patient experiencing a trauma-induced bleeding event or needing emergency surgery. 

 

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

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August 2015 Gilenya Label Change About PML Brain Infection Follows FDA Drug Safety Alert About This Serious Side Effect

These Two PML Cases Did Not Involve The Patients Previously Using The MS Drug Tysabri, As Did The One Which FDA Reported In August 2013

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

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UPDATE: On December 18, 2015 the Europeans Medicines Agency (EMA) announced it would add information about progressive multifocal leukoencephalopathy, or PML, to the Gilenya product information, along with information about basal cell carcinoma and other risks associated with Gilenya and other drugs that reduce the immune system's activity.

See: "New recommendations to minimise risks of the rare brain infection PML and a type of skin cancer with Gilenya"

(12/18/15)

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UPDATE:  "Novartis AG (NVS) Reports Third Case of PML in Relapsing MS Patient Treated with Gilenya"   (8/18/15, BioSpace)

(8/18/15)

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On August 4, 2015 the FDA posted on its web site this Safety Alert, "Gilenya (fingolimod): Drug Safety Communication - FDA Warns About Cases of Rare Brain Infection", from which we get this basic information:

ISSUE: FDA is warning that a case of definite progressive multifocal leukoencephalopathy (PML) and a case of probable PML have been reported in patients taking Gilenya (fingolimod) for multiple sclerosis (MS). These are the first cases of PML reported in patients taking Gilenya who had not been previously treated with an immunosuppressant drug for MS or any other medical condition. As a result, information about these recent cases is being added to the drug label.

BACKGROUND: Gilenya is an immunomodulator shown to benefit patients with relapsing forms of MS.  This type of MS causes attacks or relapses, which are periods of time when symptoms get worse.  Immunomodulators alter the immune system to reduce inflammation. PML is a rare and serious brain infection caused by the John Cunningham (JC) virus.  The JC virus is a common virus that is harmless in most people but can cause PML in some patients who have weakened immune systems, including those taking immunosuppressant drugs....

More detailed information about this emerging drug safety issue concerning Gilenya is found in this document, "FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs".

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We get some general context on this matter from this Reuters news report, "FDA to revise Novartis' Gilenya label to reflect brain infection risk":

PML has long been a concern associated with the long-term use of MS drugs. Sales of Biogen Inc's Tecfidera and Tysabri had been affected by reports of the rare brain infection.

Caused by a common virus that is harmless for most, PML tends to trouble patients with weakened immune systems, including those taking immunosuppressants.

The infection causes symptoms such as vision problems, confusion, as well as changes in personality, memory and orientation - potentially culminating in severe disability or death.

Gilenya was approved in 2010 to reduce relapses and delay disability progression in patients with relapsing forms of MS.

The drug raked in sales of about $700 million in the Swiss drugmaker's latest quarter.

The FDA had said in August 2013 that it was investigating a case of PML in a patient taking Gilenya, but could not conclusively link the infection to the drug as the patient had been treated with other drugs as well.

As regards the resulting August 2015 revision to the Gilenya Prescribing Information (also known as "package insert" and "drug label"), the FDA SUPPLEMENT APPROVAL letter (8/4/15) to Novartis Pharmaceuticals Corporation sets the stage:

This supplemental application provides for addition of a new subsection to the Warnings and Precautions section of the prescribing information; the new subsection [5.3] describes the cases of progressive multifocal leukoencephalopathy (PML) and probable PML that have occurred in Gilenya-treated patients. Corresponding changes have been made to the Patient Counseling Information section and the Medication Guide with respect to PML.

Here is the August 2015 Gilenya - PML warning label change information, found at this part of the current drug label (accessed 8/6/15):

5.3   Progressive Multifocal Leukoencephalopathy:

A case of progressive multifocal leukoencephalopathy (PML) and a case of probable PML occurred in patients with MS who received GILENYA in the post marketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. One patient developed PML after taking GILENYA for approximately 2.5 years. The other patient developed probable PML after taking GILENYA for approximately 4 years. The diagnosis of probable PML was based on MRI findings and the detection of JCV DNA in the CSF in the absence of clinical signs or symptoms specific to PML. The patients had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with [Tysabri (natalizumab)], which has a known association with PML. The patients were also not taking any immunosuppressive or immunomodulatory medications concomitantly. At the first sign or symptom suggestive of PML, withhold GILENYA and perform an appropriate diagnostic evaluation. MRI signs may be apparent before clinical symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

We will continue to monitor the safety profile of Gilenya as regards PML and the other serious side effects this Novartis MS drug has been associated with in recent years.

 

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

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