Drug Injury Watch

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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DrugInjuryLaw.com: Legal Information And News About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free & Confidential  (Case review done by attorney Tom Lamb) 

Pancreatic Cancer As A Side Effect Of Diabetes Drugs Bydureon, Byetta, Januvia, And Victoza

Health Canada Currently Conducting Epidemiological Study Of These Incretin-Based Type 2 Diabetes Medications To Assess This Potential Drug Safety Issue

(Posted by Tom Lamb at DrugInjuryWatch.com)

From the October 2014 edition of the Canadian Adverse Reaction Newsletter we get this drug safety review of the diabetes drugs Bydureon, Byetta, Januvia, And Victoza, "Incretin-based therapies and the risk of pancreatic cancer".

From that relatively recent Health Canada article we get this information:

Non-clinical studies have suggested that incretin-based therapies can lead to increased pancreatic cell proliferation. These findings, along with international reports of pancreatic cancer in patients using incretin-based therapies, raised concerns over the potential risk of developing pancreatic cancer with the use of these drugs.

Pancreatic cancer is the fourth leading cause of cancer death in Canada with a 5 year relative survival ratio of 8%. Risk factors for pancreatic cancer include, but are not limited to, smoking, obesity, a family history of pancreatic cancer, chronic pancreatitis and diabetes.

In 2013, Health Canada informed health care professionals that cases of pancreatic cancer had been reported internationally with the use of exenatide; no Canadian cases were reported at the time. As of July 31, 2014, Health Canada received 13 reports of pancreatic cancer suspected of being associated with all incretin-based therapies. Health Canada has not established a causal relationship between incretin-based therapies and the development of pancreatic cancer from the data currently available.

... Health Canada has initiated an epidemiological study through the Drug Safety and Effectiveness Network (DSEN) to assess the potential association between pancreatic cancer and incretin-based therapies and will continue its ongoing monitoring of this potential safety issue.

Other regulatory agencies have also reviewed the evidence regarding the pancreatic safety of incretin-based therapies and concluded that a causal association could not be established. This potential safety issue continues to be investigated internationally.

[Footnotes omitted]

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Diabetes Drugs Pancreatic Cancer 

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Among the diabetes medications in the US that fall into this class of drugs are:

• Bydureon (exenatide)
• Byetta (exenatide)
• Januvia (sitagliptin)
• Victoza (liraglutide)

In recent years, we have written previously, here, about the possible link between these diabetes drugs and cancer of the pancreas / pancreatic cancer:

Byetta / Januvia / Victoza: Update On Possible Association Between These Newer Diabetes Drugs And Pancreatic Cancer As A Side Effect

Cancer of The Pancreas: Possible Side Effect For Diabetics Who Use Byetta, Januvia, Or Victoza?

Emerging Drug Safety Issue: Possible Increased Risk Of Pancreatic Cancer With Byetta, Januvia, And Victoza — Little Is Known About Long-Term Effects

Byetta And Januvia: More Debate About The Possible Increased Risk Of Pancreatitis, Pancreatic Cancer, And Thyroid Cancer

We will watch for the results of that epidemiological study being done by Health Canada to assess the potential association between pancreatic cancer and these incretin-based diabetes drugs such as Bydureon, Byetta, Januvia, and Victoza.

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DrugInjuryLaw.com: Legal Information And News About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free & Confidential  (Case review done by attorney Tom Lamb) 

A French Medical Study Provides More Support For Apparent Link Between Benicar With Chronic Severe Diarrhea And Substantial Weight Loss Side Effects

Researchers Found An Almost 10-Times Increased Risk Of Severe Intestinal Malabsorption Associated With Benicar After 2-Years Use Compared To Some Other Blood Pressure Medications

(Posted by Tom Lamb at DrugInjuryWatch.com)

We continue to hear about patients who have been diagnosed with sprue-like enteropathy or intestinal malabsorption while using Benicar, Azor, Tribenzor, or Benicar HCT, and we have written previously about the still-emerging Benicar drug injury litigation.

In May 2014 the medical journal Gastroenterology published an article, "Severe Malabsorption Associated With Olmesartan: A French Nationwide Cohort Study", which provides some insight concerning the association between Benicar and a side effect that is often initially mistaken for celiac disease.

From the Abstract for this medical journal article about that French Benicar study:

Introduction: Several cases of severe sprue-like enteropathy have been reported in patients treated with [Benicar (Olmesartan medoxomil)], an angiotensin II receptor blocker (ARB) approved for the treatment of hypertension. The association has been questioned: in the ROADMAP phase 3-trial, the rate of diarrhea was similar in patients who received [Benicar (olmesartan)] and placebo. The objective of this study was to assess in a large, nation-wide patient cohort, the risk of severe intestinal malabsorption associated with [Benicar (olmesartan)], compared with ARBs other than [Benicar (olmesartan)] or ACEIs.

Results: 4,546,680 patients summing up to 9,010,303 person-years were included. 218 events were observed. Compared with ACEI, the adjusted rate ratio of severe intestinal malabsorption associated with [Benicar (olmesartan)] was 2.27 (95% confidence interval 1.59-3.23, p<0.0001). This adjusted rate ratio varied with treatment duration: less than 1 year RR =0.87 (95% CI 0.47- 1.6, p=0.64), between 1 and 2 years RR = 3.20 (1.58-6.46, p=0.001), 2 years or more RR= 9.53 (4.46-20.3, p<0.0001). Compared with other ARBs, the rate ratio of severe intestinal malabsorption associated with [Benicar (olmesartan)] intake was 3.0 (95% CI 2.1-4.33, p<0.0001). The risk of severe intestinal malabsorption was not significantly different between patients who were prescribed ARBs other than olmesartan and ACEIs.

Conclusion: [Benicar (olmesartan)] was associated with an increased risk of severe intestinal malabsorption. The increased risk appears after one year of treatment and reaches 9.53 after 2 years of [Benicar (olmesartan)]. ARBs other than [Benicar (olmesartan)] were not associated with an increased risk of severe intestinal malabsorption.

Our law firm is investigating these Benicar sprue-like enteropathy cases -- involving chronic severe diarrhea and substantial weight loss -- as possible products liability lawsuits against the responsible drug company, Daiichi Sankyo, Inc.

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DrugInjuryLaw.com: Legal Information And News About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free & Confidential  (Case review done by attorney Tom Lamb) 

Cialis / Levitra / Viagra - Melanoma: Possible Drug Safety Issue Was Raised And Left Open In A 2011 Medical Journal Article

Erectile Dysfunction (ED) Drugs And Pulmonary Arterial Hypertension (PAH) Medications May Cause Increased Rate Of Melanoma Metastasis

(Posted by Tom Lamb at DrugInjuryWatch.com)

To start, we get our background facts and some commentary from "Hard Times for Oncogenic BRAF-Expressing Melanoma Cells", a Preview piece in the January 2011 edition of the Cancer Cell medical journal.

• [Malignant cutaneous melanoma] progression occurs in around 20% of  cases to an aggressive, metastasizing form of the disease with extremely poor patient survival rates
• Nearly half of all melanomas carry an activating mutation in BRAF
• Recently, Marais and colleagues (Arozarena et al., 2011) have provided an extremely exciting and novel insight into the critical issue of melanoma cell invasiveness, discovering that it can be elicited by the downregulation of PDE5A
• Active-site directed selective inhibitors of this enzyme are used acutely for the treatment of penile erectile dysfunction (PED) and infantile hypertension
• This elegant study thus provides an important insight into the mechanism whereby oncogenic B-RAF promotes invasiveness in melanoma cells through a mechanism that pivotally involves PDE5A downregulation and elevation of cGMP levels

The study by Marais and colleagues mentioned in those third and fifth points, above, is the subject of this article, "Oncogenic BRAF Induces Melanoma Cell Invasion by Downregulating the cGMP-Specific Phosphodiesterase PDE5A", which appeared in that same edition of the Cancer Cell medical journal.

For an overview, we get this text from the article's Significance section:

The protein kinase BRAF is activated by somatic gain-of-function mutations in about 44% of human melanomas. This results in ERK pathway hyper-activation, and we show that this leads to downregulation of PDE5A, a cGMP-selective phosphodiesterase. PDE5A is the target of drugs such as [Viarga and Revatio (sildenafil)], [Cialis and Adcirca (tadalafil)], and [Levitra and Staxyn (vardenafil)], which are used to treat erectile dysfunction and pulmonary arterial hypertension. PDE5A downregulation by V600EBRAF induces melanoma cell invasion in vitro and in vivo and increased long-term colonization of the lungs by melanoma cells. PDE5A inhibition by sildenafil induces invasion in vitro but does not increase lung colonization. Our study establishes a link between PDE5A, cGMP, and Ca2+ metabolism, and the regulation of invasion by oncogenic BRAF in melanoma cells.

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In more detail, from the Discussion part of this 2011 Cancer Cell article:

Thus, we conclude that PDE5A is not a therapeutic target in melanoma, and our data even raise the possibility that PDE5A drugs could promote melanoma metastasis....

However, we do not perceive this to be a problem. There are no reports linking these drugs [i.e., Viagra and Revatio (sildenafil), Cialis and Adcirca (tadalafil), Levitra and Staxyn (vardenafil), and Stendra (avanafil] to increased risk of melanoma metastasis, and we found that sildenafil did not increase mouse lung colonization by melanoma cells. Furthermore, PDE5A drugs are generally used as needed rather than persistently and are generally cleared rapidly (T1/2 ∼2 hr) because their effects must be short lived.

Therefore, our data should be interpreted with care, and we do not immediately suggest that PDE5A inhibitors will drive melanoma metastasis. However, we caution that with the ever-widening clinical use of these drugs, it is not possible to discount this risk completely.

While Marais and his colleagues in this article did not associate Cialis, Levitra, Viagra, etc. with a higher rate of invasive melanoma, their medical study left the door open for there being a link between PDE5A inhibitor drugs and an increased risk of melanoma metastasis.

Then, a few years later, comes this rather high profile 2014 medical journal article about Viagra, "Sildenafil Use and Increased Risk of Incident Melanoma in US Men: A Prospective Cohort Study", published by JAMA Internal Medicine.

So, at the very least, the link between Cialis, Levitra, Viagra, etc. with a higher rate of invasive melanoma seems to remain possible, as we discussed in this November 2014 post, "The Link Between Popular Erectile Dysfunction (ED) Drug Viagra And Melanoma Has A Potential Molecular Basis According To Medical Expert Who Reviewed Recent Study".

We are currently investigating cases of melanoma in men who used Viagra, Cialis, Levitra, Staxyn, or Stendra as well as men and women who used Revatio or Adcirca, as possible drug injury lawsuits against the responsible pharmaceutical companies.

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DrugInjuryLaw.com: Legal Information And News About Prescription Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free & Confidential  (Case review done by attorney Tom Lamb)