Drug Injury Watch

Fournier's Gangrene Is A Side Effect Of Farxiga, Invokana, Jardiance, And Other SGLT2 Inhibitor Diabetes Drugs -- Or Is It?

At The Recent American Diabetes Association (ADA) Scientific Sessions There Was An Expression Of Doubt About Warnings For This Association

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In August 2018 the FDA required a new warning about an increased risk of developing Fournier’s gangrene (also known as necrotizing fasciitis of the perineum) be added to the drug labels for all SGLT2 inhibitor diabetes drugs. That regulatory action was based on 12 cases of Fournier’s gangrene reported from March 2013 to May 2018.

Next, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) issued this Drug Safety Update, "SGLT2 inhibitors: reports of Fournier’s gangrene (necrotising fasciitis of the genitalia or perineum)" in February 2019.  This MHRA document included the following statement:

An [European Union (EU)] review has assessed reported cases of Fournier’s gangrene across the class of SGLT2 inhibitors. Although diabetes mellitus is a risk factor for the development of Fournier’s gangrene, some of the EU post-marketing reports were considered possibly to be related to the use of SGLT2 inhibitors. Fournier’s gangrene usually occurs almost exclusively in men. However, around a third of the EU cases reviewed were reported in women. We are also aware of rare occurrences of Fournier’s gangrene in patients on SGLT2 inhibitors in the USA (see FDA safety announcement).

Later, an FDA analysis article published in May 2019 by the medical journal Annals of Internal Medicine presented findings from a review of 55 cases reported to the FDA Adverse Event Reporting System (FAERS) through January 2019.  Our article "FDA: More Reports Of Diabetes Drugs Invokana, Jardiance, And Farxiga Being Associated With Fournier’s Gangrene" covered this development.

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But just last month there was an expression of doubt about whether, in fact, Fournier's gangrene is a side effect of Farxiga, Invokana, and Jardiance as well as other less popular SGLT2 inhibitor diabetes drugs.

From this July 18, 2019 article published online by Medscape, "Fournier Gangrene and Genitourinary Infections With SGLT2 Inhibitors: ADA 2019 Update", we get these details:

At the recent American Diabetes Association (ADA) Scientific Sessions, more details were presented on the adverse events in DECLARE-TIMI 58, the first trial of SGLT2 inhibitors completed after the FDA warnings on FG. The investigators planned to collect serious adverse events and any adverse events leading to drug discontinuation, but went back and did an in-depth check for necrotizing fascitis in light of the concerns.

They identified six cases of FG among study participants; five occurred in the placebo group (Table). Lawrence A. Leiter, MD, University of Toronto, Ontario, Canada, said in a press conference at ADA that on the basis of the DECLARE-TIMI 58 data, SGLT2 inhibitors do not seem to increase the risk and that FG is a diabetes-associated complication.

This Medscape article included a response to that contention by Susan Bersoff-Matcha, MD, of the FDA's Center for Drug Evaluation and Research, who said the DECLARE-TIMI 58 data are still under review by the FDA. She went on to comment:

At this time, our opinion regarding the association between SGLT2 inhibitor use and FG has not changed. We, however, note that the DECLARE-TIMI 58 study only evaluated patients using [Farxiga (dapagliflozin)] and may not be reflective for the SGLT2 inhibitor drug class [as a whole].

We will continue to watch for evidence that Fournier's gangrene is Farxiga side effect as well as Invokana, Jardiance, and other SGLT2 inhibitor diabetes drugs -- or that it is not a drug side effect of these medicines.

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

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Uloric Use By Patients With Major Cardiovascular Disease Associated With Higher Risk Of Deaths

New Drug Safety Warning: Uloric Should Be Avoided When There Is Prior Myocardial Infarction, Stroke, Or Unstable Angina

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

From this Drug Safety Update issued July 17, 2019 by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA), "Febuxostat (Adenuric): increased risk of cardiovascular death and all-cause mortality in clinical trial in patients with a history of major cardiovascular disease", we get the following new Uloric warning:

Avoid treatment with [Uloric (febuxostat)] in patients with pre-existing major cardiovascular disease (for example, myocardial infarction, stroke, or unstable angina), unless no other therapy options are appropriate. Findings from a phase 4 clinical study (the CARES study) in patients with gout and a history of major cardiovascular disease show a higher risk for cardiovascular-related death and for all-cause mortality in patients assigned to [Uloric (febuxostat)] than in those assigned to allopurinol.

In Europe, a so-called "Dear Doctor Letter" about Uloric side effects was sent out in late June 2019 by the drug company responsible for Adenuric, i.e., Uloric, in agreement with the MHRA and the European Medicines Agency (EMA).

The CARES study -- or the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial -- was conducted as an FDA requirement to determine whether Uloric was noninferior to allopurinol, a long-used gout drug, with regard to major cardiovascular events in patients with gout and cardiovascular disease.

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We have written previously about Uloric causing cardiovascular death, sudden cardiac arrest or sudden cardiac death, heart failure, myocardial infarction or heart attack, stroke, unstable angina with urgent coronary revascularization, and other heart-related problems.

Our three most recent articles from earlier this year are:

• Uloric Lawsuits Involving Heart Attacks And Strokes Follow Recent FDA Warnings About Cardiovascular Deaths (April 2019)
• Uloric "Black-Box Warning" For Increased Risks Of Heart-Related Deaths And Cardiovascular Side Effects (March 2019)
• Uloric Recall, "Black-Box Warning", And Limited Use Discussed By FDA Advisory Committees In January 2019 (January 2019)

Our law firm is investigating possible Uloric lawsuits where patients have suffered cardiovascular Uloric side effects as personal injury cases or wrongful death claims, depending on the outcome.

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

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Lemtrada: Reports Of Serious Cardiovascular Events And Immune-Mediated Reactions Under Investigation

UK Drug Safety Regulator MHRA Imposes Lemtrada Use Restrictions And Mandates Patient Monitoring For Side Effects

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In May 2019 the UK's Medicines and Healthcare products Regulatory Agency (MHRA) took regulatory action regarding Lemtrada establishing new use restrictions and requiring increased monitoring of patients using this multiple sclerosis (MS) drug.

From the introductory part of this May 17, 2019 MHRA Drug Safety Update, "Lemtrada (alemtuzumab) and serious cardiovascular and immune-mediated adverse reactions: new restrictions to use and strengthened monitoring requirements", we get this summary:

While an urgent [European Union (EU)] safety review evaluates reports of serious cardiovascular events and immune-mediated reactions, including autoimmune hepatitis, the use of alemtuzumab (Lemtrada) has been restricted and strengthened requirements have been introduced to monitor vital signs and liver function before and during treatment. All patients on alemtuzumab for multiple sclerosis should be alerted to these risks and what to do if symptoms occur.

For some background on the EU safety review of Lemtrada mentioned above, we refer you to our April 2019 article "Lemtrada Review By European Drug Regulatory Agency Covers Various Serious Side Effects In MS Patients".

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Returning to the May 2019 Lemtrada Drug Safety Update from the UK's MHRA, we have compiled this list of serious side effects which have been reported in MS patients using Lemtrada "particularly within 3 days of dosing":

Cases of cardiovascular reactions

• Pulmonary hemorrhage
• Myocardial infarction
• Arterial dissection
• Stroke (hemorrhagic and ischemic)

Cases of immune-mediated disorders

• Autoimmune hepatitis
• Hemophagocytic lymphohistiocytosis

We will continue to watch for reports of serious cardiovascular events and immune-mediated reactions involving Lemtrada.

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 is done by attorney Tom Lamb)

Xeljanz Related Blood Clots Can Cause Pulmonary Embolism (PE) Or Deep Vein Thrombosis (DVT) With Patient Deaths Possible

Serious Side Effects For Xeljanz 10 mg Dose Found In Pfizer Post-Marketing Study Leads To New European Drug Safety Regulatory Action

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

The serious side effects associated with Xeljanz related blood clots first came to our attention in February 2019, at which time we wrote this earlier article, "Xeljanz Recommended Dosage For Ulcerative Colitis Patients May Increase Risk Of Pulmonary Embolism".

Less than a week later this February 25, 2019 FDA Drug Safety Communication was issued "Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate".

Then last month, in May 2019, there was more drug safety regulatory action, this time from Europe, as reported in this news report, "EMA Puts Temporary Restrictions on Tofacitinib Due to PE Risk":

The European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) is temporarily advising physicians not to prescribe the 10-mg twice-daily dose of tofacitinib (Xeljanz, Pfizer) to patients at high risk for pulmonary embolism (PE).

These include patients with heart failure, cancer, inherited coagulation disorders, a history of venous thromboembolism, either deep venous thrombosis (DVT) or PE, as well as patients taking combined hormonal contraceptives or hormone replacement therapy or who are scheduled to have major surgery.

Prescribers should also consider other factors that may increase the risk for PE, including age, obesity, smoking, or immobilization, the EMA said in a news release.

In addition, there is this Drug Safety Update article issued by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA), "Tofacitinib (Xeljanz▼): restriction of 10 mg twice-daily dose in patients at high risk of pulmonary embolism while safety review is ongoing".

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A good summary of the practical effect of the action taken in Europe is presented by this news report, "EU regulators slap safety restriction on Pfizer’s Xeljanz":

European safety regulators have placed restrictions on Pfizer’s Xeljanz, saying it should not be used in the higher dose in patients with ulcerative colitis because of concerns of increased risk of blood clots on the lung and increased mortality.

Xeljanz (tofacitinib) is approved at the higher dose of 10 mg twice daily in patients with ulcerative colitis, although this can be reduced to 5 mg twice daily in patients who respond well.

The decision means that as the 10 mg twice daily is the starting dose for all patients, no new patients should be started on the drug in ulcerative colitis....

Xeljanz is not approved in rheumatoid arthritis in Europe at the higher dose, but is available in that dose in the US, and Pfizer’s data came from a cardiovascular post-marketing safety study required by the FDA as a condition of its licence.

We point out that Xeljanz is also approved as a treatment for psoriatic arthritis that calls for a twice daily Xeljanz 5 mg dose, which is not affected by the present drug safety concerns for Xeljanz.

We will continue to monitor developments with respect to the drug safety profile of Xeljanz in the US and Europe.

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

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Gadolinium-Containing Contrast Agents Omniscan And Magnevist Being Recalled In The United Kingdom In February 2018

In Comparison, This December 2017 Regulatory Action By FDA In The US: "new class warning... for all gadolinium-based contrast agents"

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

There seems to be a consensus among the United States FDA and the United Kingdom MHRA drug safety agencies that low levels of gadolinium can be retained in the brain and other tissues after administration of gadolinium-based contrast agents (GBCAs) for months to years after receiving these drugs. 

Another point of agreement between those agencies is that certain linear GBCAs -- such as Magnevist, Omniscan, and OptiMARK -- result in more gadolinium retention in the body than macrocyclic GBCAs.

There is a difference, however, between FDA and MHRA in terms of the regulatory actions being taken with respect to this class of drugs, now.

On December 14, 2017 the Medicines and Healthcare products Regulatory Agency (MHRA) issued this document, "Gadolinium-containing contrast agents: removal of Omniscan and iv Magnevist, restrictions to the use of other linear agents", which includes the following statement:

There is currently no evidence that gadolinium deposition in the brain has caused adverse neurological effects in patients; however, licences for gadodiamide (Omniscan) and intravenous gadopentetic acid (also known as gadopentetate dimegulumine; Magnevist) will be suspended from 1 February 2018 and these products will be recalled.

Further, this MHRA document points out that "One linear agent, gadoversetamide (OptiMARK), has been withdrawn by the Marketing Authorisation Holder and is not available in the UK."

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In comparison, at the present time FDA is only requiring that there be certain changes made to the Prescribing Information, or drug label, of all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) in the US.  To be clear, none of these products will be recalled from the market here.

On December 19, 2017 this document was issued, "FDA Drug Safety Communication: FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings".

This document is an update to the May 22, 2017 MedWatch safety alert "Gadolinium-based Contrast Agents for Magnetic Resonance Imaging (MRI): Drug Safety Communication - No Harmful Effects Identified With Brain Retention".

From the December 2017 FDA Drug Safety Communication:

To date, the only known adverse health effect related to gadolinium retention is a rare condition called nephrogenic systemic fibrosis (NSF) that occurs in a small subgroup of patients with pre-existing kidney failure. We have also received reports of adverse events involving multiple organ systems in patients with normal kidney function. A causal association between these adverse events and gadolinium retention could not be established.

We are continuing to assess the health effects of gadolinium retention in the body and will update the public when new information becomes available....

Accordingly, we will be watching for any future recommendations from the FDA's Medical Imaging Drugs Advisory Committee about further label changes or regulatory actions for gadolinium-based contrast agents, especially Magnevist, Omniscan, and OptiMARK, here in the US.

DrugInjuryLaw.com: Medical & Legal 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.

 

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

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Invokana Lawsuits Are Expected To Be Filed While FDA And Other Drug Regulators Investigate Side Effects Reports

Drug Injury Lawyers Also See Possible Farxiga And Jardiance Cases For Patients Who Have Ketoacidosis, Kidney Failure, Stroke, Or Heart Attack

 

(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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With there being a growing number of Type 2 diabetes patients in the US, it is not a surprise that the pharmaceutical companies are introducing new types of diabetes medications at an increasing rate to capture market share and make profits.

One new class of new diabetes medications are Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors, which currently consist of these drugs:

Invokana (canagliflozin) -- first available in 2013
Invokamet (canagliflozin and metformin) -- first available in 2014
Farxiga (dapagliflozin) -- first available in 2014
Xigduo XR (dapagliflozin and metformin extended-release) -- first available in 2014
Jardiance (empagliflozin) -- first available in 2014
Glyxambi (empagliflozin and linagliptin) -- first available in 2015

As some of you know, often the serious side effects of new drugs are not recognized until after FDA approval and they are used by a larger patient population than was observed or studied in the earlier clinical trials.

And this seems to be the case with Invokana, Farxiga, Jardiance, and these other new diabetes drugs, as there are now numerous adverse event report which associate them with these side effects:

• Diabetic Ketoacidosis (DKA), Ketoacidosis, or Ketosis
• Heart Attacks / Myocardial Infarctions (MI)
• Ischemic Stroke / Cerebral Vascular Accident (CVA)
• Kidney Damage / Renal Failure
• Heart Failure

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And, in fact, reports of side effects related to Invokana, Farxiga, and Jardiance have gotten the attention of the FDA and other drug regulators, as can be seen by the following recent drug safety alerts:

“FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood” (May 15, 2015)

Review of diabetes medicines called SGLT2 inhibitors started — European Medicines Agency (June 12, 2015)

“Information Update – Forxiga, Invokana: Health Canada begins safety review of diabetes drugs known as SGLT2 inhibitors and risk of ketoacidosis” (June 22, 2015)

SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin): risk of diabetic ketoacidosis — Medicines and Healthcare Products Regulatory Agency (June 26, 2015)

With these investigations by drug regulators there are, also, investigations by drug injury lawyers into possible lawsuits for people with Type-2 diabetes who used one of these SGLT2 diabetes drugs and developed ketoacidosis or kidney failure, as well as when these diabetics suffer a heart attack (MI), stroke (CVA), or heart failure.

We are currently investigating possible drug injury lawsuits against the responsible pharmaceutical companies for diabetes patients who have developed any of the medical conditions listed above.

 

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

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Multiple Myeloma Drug Pomalyst Associated With Side Effects Risks Of Cardiac Failure, Interstitial Lung Disease, And Hepatotoxicity

In May 2015 The Medicines and Healthcare Products Regulatory Agency In UK Issued A Drug Safety Update; Will There Be Similar FDA Action?

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

Pomalidomide (brand name: Pomalyst in the US; Imnovid in Europe) is a multiple myeloma drug. 

In more detail, from the Celgene Corporation Prescribing information for Pomalyst (accessed 6/3/15):

POMALYST, in combination with dexamethasone, is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

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On May 20, 2015 Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom issued this Drug Safety Update, "Pomalidomide: risks of cardiac failure, interstitial lung disease and hepatotoxicity", which stated:

A review by the MHRA and other EU medicines regulators concluded that [Pomalyst (pomalidomide)] can cause interstitial lung disease (ILD), cardiac failure and hepatotoxicity. This conclusion was based on data from clinical trials, reports from clinical practice and published case reports.

This May 2015 MHRA Drug Safety Update included this detailed information about each of these Pomalyst side effects:

Cardiac failure

The review concluded that this side effect is common (ie occurs in between 1/10 and 1/100 patients who take [Pomalyst (pomalidomide)]). In most cases, this side effect occurred in patients with cardiac disease or cardiac risk factors and within 6 months of starting [Pomalyst (pomalidomide)]. The review also concluded that [Pomalyst (pomalidomide)] can cause atrial fibrillation, which may precipitate cardiac failure.

Interstitial lung disease

[Pomalyst (pomalidomide)] can cause ILD and related events such as pneumonitis. The review concluded that this side effect is common (ie occurrs in between 1/10 and 1/100 patients who take pomalidomide). Onset of respiratory symptoms is usually within 6 months of starting treatment. However, there have been cases where ILD occurred approximately 18 months after starting [Pomalyst (pomalidomide)]. ILD usually resolves with steroid treatment and stopping [Pomalyst (pomalidomide)].

Hepatotoxicity

It is already known that [Pomalyst (pomalidomide)] can elevate alanine aminotransferase and bilirubin levels. The review found that [Pomalyst (pomalidomide)] can also cause serious hepatotoxicity, mainly acute hepatitis. Hepatitis was considered an uncommon side effect (ie occurrs in between 1/100 and 1/1,000 patients who take [Pomalyst (pomalidomide)]). There have also been reports of acute liver failure in patients receiving [Pomalyst (pomalidomide)]; however the review could not determine if [Pomalyst (pomalidomide)] caused the liver failure in these cases. The risk of serious hepatic events appears to be highest in the first 6 months of treatment, therefore regular liver function monitoring is recommended during this period. The available data do not provide sufficient evidence to support specific guidance on monitoring frequency.

We will continue to monitor the safety profile of Pomalyst (pomalidomide) including watching for any similar side effects warnings by the FDA.

 

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UK Drug Safety Regulator Issues New Warnings About The Use Of Depakote / Depacon / Depakene By Women During Pregnancy

Updates Information About Extent Of Serious Developmental Disorders Such As Autism Spectrum Disorders (ASD) As Well As Congenital Malformations And Birth Defects Like Spina Bifida

(Posted by Tom Lamb at DrugInjuryWatch.com)

Depakote, Depakote CP, and Depakote ER (divalproex sodium), Depacon (valproate sodium), and Depakene (valproic acid) are manufactured and sold by the drug company AbbVie Inc. (formerly Abbott).

On January 22, 2015 the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) issued a Drug Safety Alert, "Medicines related to valproate: risk of abnormal pregnancy outcomes", which has to do with these drugs.  The subtitle of this MHRA warning was plain and clear:

• Children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and/or congenital malformations (in approximately 10% of cases).

From the "Risk of abnormal pregnancy outcomes" section of that MHRA January 2015 warning:

Valproate is associated with a dose-dependent risk of abnormal pregnancy outcomes, whether taken alone or in combination with other medicines. Data suggest that when valproate is taken for epilepsy with other medicines, the risk of abnormal pregnancy outcomes is greater than when valproate is taken alone.

The risk of congenital malformations is approximately 10% while studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking, and/or walking, have low intellectual abilities, poor language skills and memory problems.

Intelligence quotient (IQ) measured in a study of 6 years old children with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics.

Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population. Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).

And from the "Future action" section of that MHRA January 2015 warning:

The product information will now be updated to reflect our current understanding of the available evidence and to make information as clear as possible.

For more details, one can read the January 2015 MHRA Dear Doctor Letter regarding valproate medicines such as Depakote / Depacon / Depakene.

In the US, back in May 2013 there was a so-called “Black-Box” warning and several other significant label revisions about serious risks for children whose mother used Depakote / Depacon / Depakene during pregnancy which were added to the Prescribing Information by FDA and the drug company AbbVie. In part those label changes concerned higher risks of neural tube defects like spina bifida, hypospadias, and other birth defects or congenital malformations.

Then in August 2014 the Prescribing Information, or drug labels, for Depakote / Depacon / Depakene were updated by the FDA and AbbVie Inc. to add a warning about the potential risk for autism spectrum disorders (ASD).

We will watch to see if there are any further Depakote / Depacon / Depakene label changes regarding autism and/or birth defects here in the US like those that are forthcoming in the UK, according the January 2015 Drug Safety Update regarding these valproate drugs.

For more about the safety issues concerning these drugs, see our Depakote / Depakene / Depacon drug information page.

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